Modified release dosage forms

ABSTRACT

A dosage form comprises: (a) at least one active ingredient; (b) a core; and(c) a shell which surrounds the core, wherein the shell is substantially free of pores having a diameter of 0.5-5.0 microns, and the shell comprises a first shell portion and a second shell portion which are compositionally different and the dosage form provides a modified release profile of the active ingredient upon contacting of the dosage form with a liquid medium. In another embodiment, the dosage form comprises: (a) at least one active ingredient; (b) a core comprising first and second core portions; and (c) a shell which surrounds the core, wherein the shell comprises first and second shell portions such that the first shell portion resides upon the first core portion and the second shell portion resides upon the second core portion, and at least one of the first or second shell portions or first or second shell portions provides a modified release profile of the active ingredient upon contacting of the dosage form with a liquid medium.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to modified release dosage forms such asmodified release pharmaceutical compositions. More particularly, thisinvention relates to modified release dosage forms having a two-portionshell for delivering one or more active ingredients in a controlled ordelayed manner upon contacting of the dosage form with a liquid medium.

[0003] 2. Background Information

[0004] Modified release pharmaceutical dosage forms have long been usedto optimize drug delivery and enhance patient compliance, especially byreducing the number of doses of medicine the patient must take in a day.For this purpose, it is often desirable to modify the rate of release ofa drug (one particularly preferred type of active ingredient) from adosage form into the gastro-intestinal (g.i.) fluids of a patient,especially to slow the release to provide prolonged action of the drugin the body.

[0005] The rate at which an orally delivered pharmaceutical activeingredient reaches its site of action in the body depends on a number offactors, including the rate and extent of drug absorption through theg.i. mucosa. To be absorbed into the circulatory system (blood), thedrug must first be dissolved in the g.i. fluids. For many drugs,diffusion across the g.i. membranes is relatively rapid compared todissolution. In these cases, the dissolution of the active ingredient isthe rate limiting step in drug absorption, and controlling the rate ofdissolution allows the formulator to control the rate of drug absorptioninto the circulatory system of a patient.

[0006] An important objective of modified release dosage forms is toprovide a desired blood concentration versus time (pharmacokinetic, orPK) profile for the drug. Fundamentally, the PK profile for a drug isgoverned by the rate of absorption of the drug into the blood, and therate of elimination of the drug from the blood. The type of PK profiledesired depends, among other factors, on the particular activeingredient, and physiological condition being treated.

[0007] A particularly desirable PK profile for a number of drugs andconditions is one in which the level of drug in the blood is maintainedessentially constant (i.e. the rate of drug absorption is approximatelyequal to the rate of drug elimination) over a relatively long period oftime. Such systems have the benefit of reducing the frequency of dosing,improving patient compliance, as well as minimizing side effects whilemaintaining full therapeutic efficacy. A dosage form which provides a“zero-order,” or constant release rate of the drug is useful for thispurpose. Since zero-order release systems are difficult to achieve,systems which approximate a constant release rate, such as for examplefirst-order and square root of time profiles are often used to providesustained (e.g. prolonged, extended, or retarded) release of a drug.

[0008] Another particularly desirable PK profile is achieved by a dosageform that delivers a delayed release dissolution profile, in which therelease of drug from the dosage form is delayed for a pre-determinedtime after ingestion by the patient. The delay period (“lag time”) canbe followed either by prompt release of the active ingredient (“delayedburst”), or by sustained (prolonged, extended, or retarded) release ofthe active ingredient (“delayed then sustained”).

[0009] Another particularly desirable PK profile, is a “pulsatile”profile, in which for example, a first dose is delivered immediately,followed by a delay corresponding approximately to the time during whicha therapeutic concentration of the first dose is maintained in theblood, followed by either prompt or sustained release of a subsequentdose of the same drug.

[0010] It is also particularly desirable for a pharmaceutical dosageform to deliver more than one drug at a modified rate. Because the onsetand duration of the therapeutic efficacy of drugs vary widely, as dotheir absorption, distribution, metabolism, and elimination, it is oftendesirable to modify the release of different drugs in different ways, orto have a first active ingredient immediately released from the dosageform, while a second drug is released in a delayed, controlled,sustained, prolonged, extended, or retarded manner.

[0011] Well known mechanisms by which a dosage form (or drug deliverysystem) can deliver drug at a controlled rate (e.g. sustained,prolonged, extended or retarded release) include diffusion, erosion, andosmosis.

[0012] One classic diffusion-controlled release system comprises a“reservoir” containing the active ingredient, surrounded by a “membrane”through which the active ingredient must diffuse to be absorbed into thebloodstream of the patient. The rate of drug release, dM/dt depends onthe area (A) of the membrane, the diffusional pathlength (1), theconcentration gradient (ΔC) of the drug across the membrane, thepartition coefficient (K) of the drug into the membrane, and thediffusion coefficient (D):

dM/dt={ADKΔC}/1

[0013] Since one or more of the above terms, particularly thediffusional pathlength, and concentration gradient tend to benon-constant, diffusion-controlled systems generally deliver anon-constant release rate. In general, the rate of drug release fromdiffusion-controlled release systems typically follows first orderkinetics.

[0014] Another common type of diffusion-controlled release systemcomprises active ingredient, distributed throughout an insoluble porousmatrix through which the active ingredient must diffuse in order to beabsorbed into the bloodstream of the patient. The amount of drug release(M) at a given time at sink conditions (i.e. drug concentration at thematrix surface is much greater than drug concentration in the bulksolution) depends on the area (A) of the matrix, the diffusioncoefficient (D), the porosity (E) and tortuosity (T) of the matrix, thedrug solubility (Cs) in the dissolution medium, time (t) and the drugconcentration (Cp) in the dosage form:

M=A (DE/T(2Cp−ECs)(Cs)t)^(1/2)

[0015] It will be noted in the above relationship that the amount ofdrug released is generally proportional to the square root of time.Assuming factors such as matrix porosity and tortuosity are constantwithin the dosage form, a plot of amount of drug released versus thesquare root of time should be linear.

[0016] A commonly used erosion-controlled release system comprises a“matrix” throughout which the drug is distributed. The matrix typicallycomprises a material which swells at the surface, and slowly dissolvesaway layer by layer, liberating drug as it dissolves. The rate of drugrelease (dM/dt) in these systems depends on the rate of erosion (dx/dt)of the matrix, the concentration profile in the matrix, and the surfacearea (A) of the system:

dM/dt=A{dx/dt}{f(C)}

[0017] Again, variation in one or more terms, such as surface area,typically lead to a non-constant release rate of drug. In general, therate of drug release from erosion-controlled release systems typicallyfollows first order kinetics.

[0018] Another type of erosion controlled delivery system employsmaterials which swell and dissolve slowly by surface erosion to providea delayed release of pharmaceutical active ingredient. Delayed releaseis useful, for example in pulsatile or repeat action delivery systems,in which an immediate release dose is delivered, followed by apre-determined lag time before a subsequent dose is delivered from thesystem. In these systems, the lag time (T₁) depends on the thickness (h)of the erodible layer, and the rate of erosion (dx/dt) of the matrix,which in turn depends on the swelling rate and solubility of the matrixcomponents:

T ₁ =h (dx/dt)

[0019] The cumulative amount of drug (M) released from these systems ata given time generally follows the equation:

M=(dM/dt)(t−T ₁)

[0020] where dM/dt is generally described by either thediffusion-controlled or erosion-controlled equations above, and T₁ isthe lag time.

[0021] It is often practical to design dosage forms which use acombination of the above mechanisms to achieve a particularly desirablerelease profile for a particular active ingredient. It will be readilyrecognized by those skilled in the art that a dosage form constructwhich offers multiple compartments, such as for example multiple coreportions and/or multiple shell portions, is particularly advantageousfor its flexibility in providing a number of different mechanisms forcontrolling the release of one or more active ingredients.

[0022] Current core-shell systems are limited by the available methodsfor manufacturing them, as well as the materials that are suitable foruse with the current methods. A shell, or coating, which confersmodified release properties is typically applied via conventionalmethods, such as for example, spray-coating in a coating pan.Pan-coating produces a single shell which essentially surrounds thecore. The single shell is inherently limited in its functionality. It ispossible via pan-coating to apply multiple concentric shells, each witha different functionality, however such systems are limited in that theouter shell must first dissolve before the functionality conferred byeach successive layer can be realized. It is also known, via pancoating, to deliver a first dose of active ingredient from a coating,and a second dose of active ingredient from a core. Dosage forms havingsprayed coatings which provide delayed release are described, forexample, in G. Maffione et al., “High-Viscosity HPMC as a Film-CoatingAgent,” Drug Development and Industrial Pharmacy (1993) 19(16), pp.2043-2053. U.S. Pat. No. 4,576,604, for example, discloses an osmoticdevice (dosage form) comprising a drug compartment surrounded by a wall(coating) in which the coating may comprise an immediate release dose ofdrug, and the inner drug compartment may comprise a sustained releasedose of drug. The coating compositions that can be applied via sprayingare limited by their viscosity. High vicosity solutions are difficult orimpractical to pump and deliver through a spray nozzle. Spray coatingmethods suffer the further limitations of being time-intensive andcostly. Several hours of spraying may be required to spray an effectiveamount of coating to control the release of an active ingredient.Coating times of 8 to 24 hours are not uncommon.

[0023] Alternately, conventional modifed release systems may be preparedby compression, to produce either multiple stacked layers, or core andshell configurations. Modified release dosage forms prepared viacompression are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200,and WO 99/51209. It is possible, via compression-coating, to produce a2-portion shell, which may function as a barrier, or release delayingcoating, however compression-coated systems are limited by the shellthickness and shell composition. Gunsel et al., “Compression-coated andlayer tablets” in Pharmaceutical Dosage Forms—Tablets, edited by H. A.Lieberman, L. Lachman, J. B. Schwartz (2nd ed., rev. and expanded.Marcel Dekker, Inc.) pp. 247-284, for example discloses the thickness ofcompression coated shells is typically between 800 and 1200 microns.Because of these limitations, compression-coated dosage forms are notoptimal for providing certain types of modified release, such as forexample diffusion-controlled release which is not preceded by alag-time. U.S. Pat. No. 5,738,874, discloses a 3-layer pharmaceuticalcompressed tablet capable of liberating one or more drugs at differentrelease rates, in which an immediate release dose of active may becontained in a compressed coating layer, and the compressed coatinglayer has a weight which is 230% to 250% of the weight of the core, anda sustained release dose of active ingredient is contained in the core.Alternatively the outer compressed coating layer may function via anerosion mechanism to delay release of an active ingredient contained inthe core. U.S. Pat. No. 5,464,633, for example, disclosesdelayed-release dosage forms in which an extermal coating layer wasapplied by a compression coating process. The coating level ranged from105 percent to 140 percent of the weight of the core in order to yieldproduct with the desired time delayed profile.

[0024] It is one object of this invention to provide a dosage form inwhich at least one active ingredient contained therein exhibits amodified release profile upon contacting of the dosage form with aliquid medium. Other objects, features and advantages of the inventionwill be apparent to those skilled in the art from the detaileddescription set forth below.

SUMMARY OF THE INVENTION

[0025] In one embodiment, the dosage form of this invention comprises:(a) at least one active ingredient; (b) a core; and (c) a shell whichresides upon at least a portion of the core, wherein the shell issubstantially free of pores having a diameter of 0.5 to 5.0 microns, theshell comprises a first shell portion and a second shell portion whichare compositionally different and the dosage form provides a modifiedrelease profile of the active ingredient upon contacting of the dosageform with a liquid medium.

[0026] In another embodiment, the dosage form of this inventioncomprises: (a) at least one active ingredient; (b) a core comprisingfirst and second core portions; and (c) a shell portion which surroundsat least one of the first or second core portions.

[0027] In another embodiment, the dosage form of this inventioncomprises: (a) at least one active ingredient; (b) a core comprisingfirst and second core portions; and (c) a shell portion which surroundsonly the first core portion, wherein the second core portion is notenclosed by a shell portion, and is exposed immediately to the liquidmedium upon contact of the dosage form with a liquid medium.

[0028] In another embodiment, the dosage form of this inventioncomprises: (a) at least one active ingredient; (b) a core comprisingfirst and second core portions; and (c) a shell which resides upon atleast a portion of the core, wherein the shell comprises first andsecond shell portions such that the first shell portion resides upon atleast a portion of the first core portion and the second shell portionresides upon at least a portion of the second core portion, and at leastone of the first or second core portions or first or second shellportions provides a modified release profile of an active ingredientupon contacting of the dosage form with a liquid medium.

[0029] In another embodiment, at least one of the first or second shellportions comprises an active ingredient.

[0030] In another embodiment, the first and second shell portions eachcomprise an active ingredient.

[0031] In another embodiment, at least one of the first or second shellportions comprises an active ingredient which is immediately releasedtherefrom upon contacting of the dosage form with a liquid medium.

[0032] In another embodiment, at least one of the first or second shellportions provides modified release of at least one active ingredientcontained therein.

[0033] In another embodiment, at least one of the first or second shellportions comprises at least one active ingredient, and the release ofthe active ingredient contained in the shell portion is sustained,prolonged, extended, or retarded upon contacting of the dosage form witha liquid medium.

[0034] In another embodiment, the first and second shell portions eachprovide different release profiles for the active ingredients containedtherein upon contacting of the dosage form with a liquid medium.

[0035] In another embodiment, at least one of the first or second shellportions provides modified release of at least one active ingredientcontained in the underlying core or portion thereof.

[0036] In another embodiment, the core comprises particles comprising atleast one active ingredient.

[0037] In another embodiment, the particles comprise a coating capableof providing a modified release profile of the active ingredient in theparticles upon contacting of the core with a liquid medium.

[0038] In another embodiment, the core comprises a first core portionand a second core portion, at least one core portion comprises at leastone active ingredient, and at least one active ingredient contained inthe first or second core portion exhibits a modified release profileupon contacting of the dosage form with a liquid medium.

[0039] In another embodiment, the core comprises a first core portionand a second core portion, at least one core portion comprises at leastone active ingredient, and the materials comprising the first or secondcore portion provide a modification to the release of an activeingredient contained therein upon contacting of the dosage form with aliquid medium.

[0040] In another embodiment, the core comprises a first core portionand a second core portion, at least one core portion comprises at leastone active ingredient, and the materials comprising the first or secondshell portion provide a modification to the release of an activeingredient contained in the underlying core portion upon contacting ofthe dosage form with a liquid medium.

[0041] In another embodiment, the core comprises a first core portionand a second core portion, at least one core portion comprises at leastone active ingredient, and the release of the active ingredientcontained in the core portion is delayed upon contacting of the dosageform with a liquid medium.

[0042] In another embodiment, the core comprises a first core portionand a second core portion, at least one core portion comprises at leastone active ingredient, and the release of the active ingredientcontained in the core portion is sustained, prolonged, extened, orretarded upon contacting of the dosage form with a liquid medium.

[0043] In another embodiment, at least one of the first or second coreportions comprises an active ingredient which is immediately releasedtherefrom upon breach of the surrounding shell portion and contacting ofthe core portion with a liquid medium.

[0044] In another embodiment, the core comprises a first core portionand a second core portion, each core portion comprises an activeingredient, and each of the active ingredients exhibits a modifiedrelease profile upon contacting of the dosage form with a liquid medium.

[0045] In another embodiment, the release profiles of the activeingredients in the first and second core portions are substantiallysimilar.

[0046] In another embodiment, the release profiles of the first andsecond core portions are substantially different.

[0047] In another embodiment, the core comprises a first core portionand a second core portion, only one of the first or second core portionscomprises one or more active ingredients, and at least one activeingredient exhibits a modified release profile upon contacting of thedosage form with a liquid medium.

[0048] In another embodiment, the core is a bi-layer tablet.

[0049] In another embodiment, at least one of the first or second coreportions comprises particles comprising at least one active ingredient.

[0050] In another embodiment, the particles comprise a coating capableof providing a modifed release profile of the active ingredient in theparticles upon contacting of the core with a liquid medium.

[0051] In another embodiment, the core is substantially free of poreshaving a diameter of 0.5-5.0 microns.

[0052] In another embodiment, the first core portion comprises a firstactive ingredient, and the second core portion does not comprise anactive ingredient.

[0053] In another embodiment, the first core portion comprises a firstactive ingredient, and the second core portion comprises a second activeingredient.

[0054] In another embodiment, the first shell portion provides formodified release of the first active ingredient, and the second shellportion provides for modified release of the second active ingredient.

[0055] In another embodiment, the first shell portion provides forimmediate release of the first active ingredient, and the second shellportion provides for modified release of the second active ingredient.

[0056] In another embodiment, the first core portion comprises a firstactive ingredient, the second core portion comprises a second activeingredient, the first shell portion comprises a third active ingredient,and the second shell portion comprises a fourth active ingredient.

[0057] In another embodiment, at least one of the first or second coreportions is substantially free of pores having a diameter of 0.5-5.0microns.

[0058] In another embodiment, at least one of the first or second shellportions is substantially free of pores having a diameter of 0.5-5.0microns.

[0059] In another embodiment, one or more shell portions functions as abarrier to prevent release therethrough of an active ingredientcontained in the underlying core or core portion.

[0060] In another embodiment, at least one of the first or second shellportions comprises a thermal-reversible carrier selected from the groupconsisting of polyethylene glycol, polyethylene oxide and combinationsthereof.

[0061] In another embodiment, at least one of the first or second shellportions comprises a release modifying excipent selected from the groupconsisting of shellac, hydroxypropylmethylcellulose, polyethylene oxide,ammonio methacrylate copolymer type B, and combinations thereof.

[0062] In another embodiment, at least one of the first or second shellportions comprises a film-former selected from the group consisting ofcellulose acetate, ammonio methacrylate copolymer type B, shellac,hydroxypropylmethylcellulose, and combinations thereof.

[0063] In another embodiment, at least one of the first or second shellportions comprises a swellable erodible hydrophilic material selectedfrom the group consisting of selected from cross-linked polyvinylpyrrolidone, cross-linked agar, cross-linked carboxymethylcellosesodium, and combinations thereof.

[0064] In another embodiment, at least one of the first or second shellportions further comprises a plasticizer.

[0065] In another embodiment, at least one of the first or second shellportions comprises a pore former.

[0066] In another embodiment, an outer coating covers at least a portionof the shell.

[0067] In another embodiment, the shell is prepared using a solvent-freemolding process.

[0068] In another embodiment, the shell comprises at least 30% by weightof a thermal-reversible carrier.

[0069] In another embodiment, the shell comprises up to 55% by weight ofa swellable, erodible hydrophilic material.

[0070] In another embodiment, the shell is prepared using asolvent-based molding process.

[0071] In another embodiment, the shell comprises at least 15% by weightof a film-former.

[0072] In another embodiment, the shell comprises at least 55% by weightof a release-modifying agent.

BRIEF DESCRIPTION OF THE DRAWINGS

[0073]FIG. 1 depicts a cross-sectional side view of one embodiment ofthe dosage form of this invention.

[0074]FIG. 2 depicts a cross-sectional side view of another embodimentof the dosage form of this invention.

[0075]FIG. 3 depicts the % release of active ingredient vs. timemeasured for the dosage form of Example 1.

[0076]FIG. 4 depicts the % release of active ingredient vs. timemeasured for the dosage form of Example 2.

DETAILED DESCRIPTION OF THE INVENTION

[0077] As used herein, the term “dosage form” applies to any solidobject, semi-solid, or liquid composition designed to contain a specificpre-determined amount (dose) of a certain ingredient, for example anactive ingredient as defined below. Suitable dosage forms may bepharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical ormucosal delivery, or subcutaneous implants, or other implanted drugdelivery systems; or compositions for delivering minerals, vitamins andother nutraceuticals, oral care agents, flavorants, and the like.Preferably the dosage forms of the present invention are considered tobe solid, however they may contain liquid or semi-solid components. In aparticularly preferred embodiment, the dosage form is an orallyadministered system for delivering a pharmaceutical active ingredient tothe gastro-intestinal tract of a human.

[0078] The dosage forms of the invention exhibit modified release of oneor more active ingredients contained therein. The active ingredient oringredients may be found within the core, the shell, or a portion orcombination thereof. As used herein, the term “modified release” shallapply to dosage forms, coatings, shells, cores, portions thereof, orcompositions that alter the release of an active ingredient in anymanner. The active ingredient or ingredients that are released in amodified manner may be contained within the coating, shell, core,composition, or portion thereof providing the modification.Alternatively the modified release active ingredient may be contained ina different portion of the dosage form from the coating, shell, core,composition, or portion thereof providing the modification; for examplethe modified release active ingredient may be contained in a coreportion, and the modification may be provided by the overlaying shellportion. Types of modified release include controlled, prolonged,sustained, extended, delayed, pulsatile, repeat action, and the like.Suitable mechanisms for achieving these types of modified releaseinclude diffusion, erosion, surface area control via geometry and/orimpermeable barriers, or other mechanisms known in the art. Moreover,the modified release properties of the dosage form may be achievedthrough design of the core or a portion thereof, or the first shellportion, or the second shell portion, or a combination of two or more ofthese parts of the dosage form.

[0079] The dissolution profile of each active ingredient from the dosageform may be governed by a sum of contributions from the properties ofthe various portions. Additionally, a single portion, for example a coreportion, may possess a combination of erosional and diffusionalproperties. In any case, the dissolution rate of a particular activeingredient from the dosage form will be the sum of the contributionsfrom all the various mechanisms contributed by the various portions ofthe dosage form which effect the release of that particular activeingredient, as depicted by the following equation:

Rate_(total) . . . = . . . X ₁Rate₁ . . . +X ₂Rate₂ . . . +X ₃Rate₃ . .. +X _(n)Rate_(n)

[0080] where X₁, X₂, X₃, . . . X_(n) are the relative contributionfractions of to the total release rate, and Rate₁, Rate₂, Rate₃, . . .Rate_(n) are the various release rates contributed by effects of thevarious portions of the dosage form on a particular active ingredient.

[0081] Suitable active ingredients for use in this invention include forexample pharmaceuticals, minerals, vitamins and other nutraceuticals,oral care agents, flavorants and mixtures thereof. Suitablepharmaceuticals include analgesics, anti-inflammatory agents,antiarthritics, anesthetics, antihistamines, antitussives, antibiotics,anti-infective agents, antivirals, anticoagulants, antidepressants,antidiabetic agents, antiemetics, antiflatulents, antifungals,antispasmodics, appetite suppressants, bronchodilators, cardiovascularagents, central nervous system agents, central nervous systemstimulants, decongestants, oral contraceptives, diuretics, expectorants,gastrointestinal agents, migraine preparations, motion sicknessproducts, mucolytics, muscle relaxants, osteoporosis preparations,polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tractagents and mixtures thereof.

[0082] Suitable oral care agents include breath fresheners, toothwhiteners, antimicrobial agents, tooth mineralizers, tooth decayinhibitors, topical anesthetics, mucoprotectants, and the like.

[0083] Suitable flavorants include menthol, peppermint, mint flavors,fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors,liqueur flavors and combinations and the like.

[0084] Examples of suitable gastrointestinal agents include antacidssuch as calcium carbonate, magnesium hydroxide, magnesium oxide,magnesium carbonate, aluminum hydroxide, sodium bicarbonate,dihydroxyaluminum sodium carbonate; stimulant laxatives, such asbisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,castor oil, ricinoleic acid, and dehydrocholic acid, and mixturesthereof; H2 receptor antagonists, such as famotadine, ranitidine,cimetadine, nizatidine; proton pump inhibitors such as omeprazole orlansoprazole; gastrointestinal cytoprotectives, such as sucraflate andmisoprostol; gastrointestinal prokinetics, such as prucalopride,antibiotics for H. pylori, such as clarithromycin, amoxicillin,tetracycline, and metronidazole; antidiarrheals, such as diphenoxylateand loperamide; glycopyrrolate; antiemetics, such as ondansetron,analgesics, such as mesalamine.

[0085] In one embodiment of the invention, the active ingredient may beselected from bisacodyl, famotadine, ranitidine, cimetidine,prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth,antacids, and pharmaceutically acceptable salts, esters, isomers, andmixtures thereof.

[0086] In another embodiment, the active ingredient is selected fromanalgesics, anti-inflammatories, and antipyretics, e.g. non-steroidalanti-inflammatory drugs (NSAIDs), including propionic acid derivatives,e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acidderivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and thelike; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid,flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g.diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam,sudoxicam, isoxicam, meloxicam, and the like. In a particularlypreferred embodiment, the active ingredient is selected from propionicacid derivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen,oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts,derivatives, and combinations thereof. In a particular embodiment of theinvention, the active ingredient may be selected from acetaminophen,acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen,diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

[0087] In another embodiment of the invention, the active ingredient maybe selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine,dextromethorphan, diphenhydramine, astemizole, terfenadine,fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereofand pharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

[0088] Examples of suitable polydimethylsiloxanes, which include, butare not limited to dimethicone and simethicone, are those disclosed inU.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of eachis expressly incorporated herein by reference. As used herein, the term“simethicone” refers to the broader class of polydimethylsiloxanes,including but not limited to simethicone and dimethicone.

[0089] The active ingredient or ingredients are present in the dosageform in a therapeutically effective amount, which is an amount thatproduces the desired therapeutic response upon oral administration andcan be readily determined by one skilled in the art. In determining suchamounts, the particular active ingredient being administered, thebioavailability characteristics of the active ingredient, the dosingregimen, the age and weight of the patient, and other factors must beconsidered, as known in the art. Typically, the dosage form comprises atleast about 1 weight percent, preferably, the dosage form comprises atleast about 5 weight percent, e.g. about 20 weight percent of acombination of one or more active ingredients. In one preferredembodiment, the core comprises a total of at least about 25 weightpercent (based on the weight of the core) of one or more activeingredients.

[0090] The active ingredient or ingredients may be present in the dosageform in any form. For example, the active ingredient may be dispersed atthe molecular level, e.g. melted or dissolved, within the dosage form,or may be in the form of particles, which in turn may be coated oruncoated. If the active ingredient is in form of particles , theparticles (whether coated or uncoated) typically have an averageparticle size of about 1-2000 microns. In one preferred embodiment, suchparticles are crystals having an average particle size of about 1-300microns. In another preferred embodiment, the particles are granules orpellets having an average particle size of about 50-2000 microns,preferably about 50-1000 microns, most preferably about 100-800 microns.

[0091] In embodiments where an active ingredient is contained within thecore, at least a portion of the active ingredient may be optionallycoated with a release-modifying coating, as known in the art. Thisadvantageously provides an additional tool for modifying the releaseprofile of active ingredient from the dosage form. For example, the coremay contain coated particles of one or more active ingredients, in whichthe particle coating confers a release modifying function, as is wellknown in the art. Examples of suitable release modifying coatings forparticles are described in U.S. Pat. Nos. 4,173,626; 4,863,742;4,980,170; 4,984,240; 5,286,497; 5,912,013; 6,270,805; and 6,322,819.Commercially available modified release coated active particles may alsobe employed. Accordingly, all or a portion of one or more activeingredients in the core may be coated with a release-modifying material.

[0092] In embodiments in which it is desired for the active ingredientto be absorbed into the systemic circulation of an animal, the activeingredient or ingredients are preferably capable of dissolution uponcontact with a fluid such as water, gastric fluid, intestinal fluid orthe like. In one embodiment, the dissolution characteristics of at leastone active ingredient meets USP specifications for immediate releasetablets containing the active ingredient. For example, for acetaminophentablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USPapparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophencontained in the dosage form is released therefrom within 30 minutesafter dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the ibuprofen contained in the dosage form is released therefromwithin 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856(1999). In embodiments in which at least one active ingredient isreleased immediately, the immediately released active ingredient ispreferably contained in the shell or on the surface of the shell, e.g.in a further coating surrounding at least a portion of the shell. Inanother embodiment, the dissolution characteristics of one or moreactive ingredients are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like. In a preferred embodiment inwhich one or more active ingredients are released in a modified manner,the modified release active or actives are preferably contained in thecore.

[0093] A first embodiment of this invention is depicted in FIG. 1, whichis a cross-sectional side view of a dosage form 2 which comprises a core4 and first and second shell portions 6 and 8, respectively, which inthis embodiment surround the core. In other embodiments of thisinvention, the first and second shell portions 6 and 8 may reside upon aportion of the core 4 without surrounding the core 4.

[0094] A second embodiment of this invention is depicted in FIG. 2,which is a cross-sectional side view of a dosage form 202 whichcomprises a core 204 having first and second portions 203 and 205,respectively, and first and second shell portions 206 and 208,respectively, which in this embodiment surround the core. In otherembodiments of this invention, the first and second shell portions 206and 208 may reside upon first and second core portions 203 and 205,respectively, without surrounding the core 204.

[0095] In certain embodiments of the invention, one or more shellportions contain active ingredient which is released essentiallyimmediately upon ingestion of the dosage form. In these embodiments, theshell portion preferably comprises materials which exhibit rapiddissolution in gastro-intestinal fluids.

[0096] In certain other embodiments, one or more shell portions functionas a diffusional membrane which contains pores through which fluids canenter the dosage form, and dissolved active ingredient can be releasedin a sustained, extended, prolonged or retarded manner. In theseembodiments, the rate of release of active ingredient from an underlyingcore portion will depend upon the total pore area in the shell portion,the pathlength of the pores, and the solubility and diffusivity of theactive ingredient (in addition to its rate of release from the coreportion itself). In preferred embodiments in which a shell portionfunctions as a diffusional membrane, the release of the activeingredient from the dosage form may be described as controlled,prolonged, sustained or extended. In these embodiments, the contributionto active ingredient dissolution from the subject shell portion mayfollow zero-order, first-order, or square-root of time kinetics. Incertain such embodiments, the diffusional membrane shell portionpreferrably comprises a release-modifying excipient such as acombination of a pore former and an insoluble edible material such asfor example a film forming water insoluble polymer. Alternately, in suchembodiments in which the shell portion is prepared by solven-freemolding, the thermal-reversible carrier may function by dissolving andforming pores or channels through which the active ingredient may beliberated.

[0097] In certain other embodiments, one or more shell portions functionas an eroding matrix from which active ingredient dispersed in the shellportion is liberated by the dissolution of successive layers of theshell portion surface. In these embodiments, the rate of activeingredient release will depend on the dissolution rate of the matrixmaterial in the shell portion. Particularly useful matrix materials forproviding surface erosion include those which first absorb liquid, thenswell and/or gel prior to dissolving. In certain such embodiments, theeroding matrix shell portion preferably comprises a swellable erodiblehydrophilic material.

[0098] In certain other embodiments, one or more shell portions functionas a barrier to prevent release therethrough of an active ingredientcontained in the underlying core or core portion. In such embodiments,active ingredient is typically released from a portion of the core whichis not covered by the barrier shell portion. Such embodimentsadvantageously allow for control of the surface area for release of theactive ingredient. In certain particular embodiments, for example, thesurface area for release of active ingredient can be maintainedsubstantially constant over time. In a particularly preferredembodiment, the release of at least one active ingredient followssubstantially zero-order kinetics. In certain such embdiments, thebarrier shell portion preferably comprises a water insoluble materialsuch as for example a water insoluble polymer.

[0099] In certain other embodiments, one or more shell portions functionas a delayed release coating to delay release of an active ingredientwhich is contained in the core or a portion thereof. In theseembodiments, the lag-time for onset of active ingredient release may begoverned by erosion of the coating or diffusion through the coating or acombination thereof. In certain such embodiments, the eroding matrixshell portion preferably comprises a swellable erodible hydrophilicmaterial.

[0100] In embodiments in which one or more shell portions function tomodify the release of an active ingredient which is contained in thecore or the subject shell portion, the thickness of the shell portion iscritical to the release properties of the dosage form. Advantageouslythe dosage forms of the invention can be made with precise control overshell thickness. In a preferred embodiment in which one or more shellportions function to modify the release of an active ingredient which iscontained in the core or the subject shell portion, the shell portion orportions are made by the thermal cycle or thermal setting injectionmolding methods and apparatus described below.

[0101] In certain embodiments of the invention, one or more coreportions function to promptly, e.g. immediately, release one or moreactive ingredients contained therein upon breach of the surroundingshell portion. In these embodiments, the core portion preferablycomprises materials which exhibit rapid dissolution in gastro-intestinalfluids, for example the core portion may comprise a disintegrant.

[0102] In certain other embodiments, one or more core portions functionas an eroding matrix from which dispersed active ingredient is liberatedby the dissolution of successive layers of the matrix surface. In theseembodiments, the rate of active ingredient release from the core portionwill depend on the dissolution rate of the matrix material. Particularlyuseful eroding matrix materials for providing surface erosion includethose which first absorb liquid, then swell and/or gel prior todissolving. In certain such embodiments, the eroding matrix core portionpreferrably comprises a swellable erodible hydrophilic material.

[0103] In certain other embodiments, one or more core portions functionas a diffusional matrix. In these embodiments, the core portionpreferably comprises active ingredient, distributed throughout aninsoluble porous matrix, which contains pores or channels through whichfluids can enter the core portion, and the active ingredient mustdiffuse to be released from the dosage form. In these embodiments, therate of active ingredient release from the core portion will depend uponthe area (A) of the matrix, the diffusion coefficient (D), the porosity(E) and tortuosity (T) of the matrix, the drug solubility (Cs) in thedissolution medium, and the drug concentration (Cp) in the dosage form.In preferred embodiments in which a core portion functions as adiffusional matrix, the release of the active ingredient from the coreportion may be described as controlled, prolonged, sustained, orextended. In these embodiments, the contribution to active ingredientdissolution from the subject core portion may follow zero-order,first-order, or preferably square-root of time kinetics. In certain suchembodiments, the diffusional matrix core portion preferably comprises apore former.

[0104] In embodiments in which a core portion functions to modifyrelease of an active ingredient contained therein, the release of activeingredient may be further modified by the function of a surroundingshell portion, as described above. In such embodiments, the release ofthe active ingredient from the dosage form will be governed by the sumof all the contributions acting upon it, e.g. from the relevant core andshell portions, and may be described as controlled, prolonged,sustained, extended, delayed, or pulsatile. In these embodiments, thedissolution of active ingredient from the dosage form may followzero-order, first-order, or square-root of time kinetics.

[0105] In embodiments in which the core comprises multiple portions, theportions may comprise different materials, or be prepared by differentmethods, or both. In one particular embodiment a first core portion maybe prepared by compression, and a second core portion may be prepared bymolding.

[0106] In certain preferred embodiments, the core comprises multipleportions, which comprise different active ingredients or have differentrelease-modifying properties, or both; and the shell comprises acorresponding number of multiple portions, which each cover a specificcore portion in order to modify or further modify the release of one ormore active ingredients contained within the respective core portion.For such embodiments, it is critical to have a manufacturing processwhich is capable of maintaining the orientation of the core prior to andduring the application of each shell portion thereon. Advantageously,the orientation of the components of the dosage forms of the presentinvention can be precisely controlled, when manufactured using thethermal cycle and thermal setting apparatus and described below. In onesuch particularly preferred embodiment, the dosage form comprises a corecomprising a first core portion and a second core portion which arecompositionally different, wherein at least one of the first or secondcore portions comprises an active ingredient; and a shell whichsurrounds the core and comprises a first shell portion and a secondshell portion which are compositionally different, wherein at least oneof the first or second shell portions confers a modification to therelease of an active ingredient contained in the underlying coreportion.

[0107] In certain other embodiments of the invention, a further degreeof flexibility in designing the dosage forms of the present inventioncan be achieved through the use of an additional outer coatingoverlaying the shell or one or more portions thereof. The additionalouter coating may be applied for example by compression, or by molding.In such embodiments, the dosage form of the invention comprises at leastone active ingredient; a core; a shell which resides upon at least aportion of the core and comprises a first and second shell portion whichare compositionally different; and an outer coating which covers atleast a portion of the shell. The outer coating may for example cover aportion of the first shell portion, or the second shell portion, orboth, or may surround the entire shell. In one particularly preferredembodiment, the outer coating comprises an active ingredient, which isreleased immediately (i.e. the dissolution of the active ingredient fromthe outer coating conforms to USP specifications for immediate releasedosage forms of the particular active ingredient employed). In one suchparticularly preferred embodiment, the dosage form is a pulsatile drugdelivery system, in which one or more shell portions provides fordelayed release of a second dose of active ingredient, which iscontained in an underlying core portion.

[0108] The core of the present invention may be prepared by any suitablemethod, including for example compression and molding, and depending onthe method by which it is made, typically comprises active ingredientand a variety of excipients (inactive ingredients which may be usefulfor conferring desired physical properties to the dosage core).

[0109] In embodiments in which the core, or a portion thereof, is madeby compression, suitable excipients include fillers, binders,disintegrants, lubricants, glidants, and the like, as known in the art.In embodiments in which the core is made by compression and additionallyconfers modified release of an active ingredient contained therein, thecore preferably further comprises a release-modifying compressibleexcipient.

[0110] Suitable fillers for use in making the core, or a portionthereof, by compression include water-soluble compressible carbohydratessuch as sugars, which include dextrose, sucrose, maltose, and lactose,sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol,starch hydrolysates, which include dextrins, and maltodextrins, and thelike, water insoluble plastically deforming materials such asmicrocrystalline cellulose or other cellulosic derivatives,water-insoluble brittle fracture materials such as dicalcium phosphate,tricalcium phosphate and the like and mixtures thereof.

[0111] Suitable binders for making the core, or a portion thereof, bycompression include dry binders such as polyvinyl pyrrolidone,hydroxypropylmethylcellulose, and the like; wet binders such aswater-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose,starches, and the like; and derivatives and mixtures thereof.

[0112] Suitable disintegrants for making the core, or a portion thereof,by compression, include sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and the like.

[0113] Suitable lubricants for making the core, or a portion thereof, bycompression include long chain fatty acids and their salts, such asmagnesium stearate and stearic acid, talc, glycerides and waxes.

[0114] Suitable glidants for making the core, or a portion thereof, bycompression, include colloidal silicon dioxide, and the like.

[0115] Suitable release-modifying compressible excipients for making thecore, or a portion thereof, by compression include swellable erodiblehydrophillic materials, insoluble edible materials, pH-dependentpolymers, and the like.

[0116] Suitable swellable erodible hydrophilic materials for use asrelease-modifying excipients for making the core, or a portion thereof,by compression include: water swellable cellulose derivatives,polyalkalene glycols, thermoplastic polyalkalene oxides, acrylicpolymers, hydrocolloids, clays, gelling starches, and swellingcross-linked polymers, and derivitives, copolymers, and combinationsthereof. Examples of suitable water swellable cellulose derivativesinclude sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples ofsuitable polyalkalene glyclols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkalene oxides include poly (ethyleneoxide). Examples of suitable acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL(high-molceular weight cross-linked acrylic acid homopolymers andcopolymers), and the like. Examples of suitable hydrocolloids includealginates, agar, guar gum, locust bean gum, kappa carrageenan, iotacarrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellangum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan,chitin, cyclodextrin, chitosan. Examples of suitable clays includesmectites such as bentonite, kaolin, and laponite; magnesiumtrisilicate, magnesium aluminum silicate, and the like, and derivativesand mixtures thereof. Examples of suitable gelling starches include acidhydrolyzed starches, swelling starches such as sodium starch glycolate,and derivatives thereof. Examples of suitable swelling cross-linkedpolymers include cross-linked polyvinyl pyrrolidone, cross-linked agar,and cross-linked carboxymethylcellose sodium.

[0117] Suitable insoluble edible materials for use as release-modifyingexcipients for making the core, or a portion thereof, by compressioninclude water-insoluble polymers, and low-melting hydrophobic materials.Examples of suitable water-insoluble polymers include ethylcellulose,polyvinyl alcohols, polyvinyl acetate, polycaprolactones, celluloseacetate and its derivatives, acrylates, methacrylates, acrylic acidcopolymers; and the like and derivatives, copolymers, and combinationsthereof. Suitable low-melting hydrophobic materials include fats, fattyacid esters, phospholipids, and waxes. Examples of suitable fats includehydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil; and free fatty acids andtheir salts. Examples of suitable fatty acid esters include sucrosefatty acid esters, mono, di, and triglycerides, glyceryl behenate,glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate,glyceryl trilaurylate, glyceryl myristate, Glyco Wax-932, lauroylmacrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples ofsuitable phospholipids include phosphotidyl choline, phosphotidylserene, phosphotidyl enositol, and phosphotidic acid. Examples ofsuitable waxes include camauba wax, spermaceti wax, beeswax, candelillawax, shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate; and the like.

[0118] Suitable pH-dependent polymers for use as release-modifyingexcipients for making the core, or a portion thereof, by compressioninclude enteric cellulose derivatives, for example hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, cellulose acetate phthalate; natural resins such as shellacand zein; enteric acetate derivatives such as for examplepolyvinylacetate phthalate, cellulose acetate phthalate, acetaldehydedimethylcellulose acetate; and enteric acrylate derivatives such as forexample polymethacrylate-based polymers such as poly(methacrylic acid,methyl methacrylate) 1:2, which is commercially available from RohmPharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid,methyl methacrylate) 1:1, which is commercially available from RohmPharma GmbH under the tradename EUDRAGIT L, and the like, andderivatives, salts, copolymers, and combinations thereof.

[0119] Suitable pharmaceutically acceptable adjuvants for making thecore, or a portion thereof, by compression include, preservatives; highintensity sweeteners such as aspartame, acesulfame potassium, sucralose,and saccharin; flavorants; colorants; antioxidants; surfactants; wettingagents; and the like and mixtures thereof.

[0120] In one embodiment, the core is prepared by the compressionmethods and apparatus described in copending U.S. patent applicationSer. No. 09/966,509, pages 16-27, the disclosure of which isincorporated herein by reference. Specifically, the core is made using arotary compression module comprising a fill zone, insertion zone,compression zone, ejection zone, and purge zone in a single apparatushaving a double row die construction as shown in FIG. 6 of U.S. patentapplication Ser. No. 09/966,509. The dies of the compression module arepreferably filled using the assistance of a vacuum, with filters locatedin or near each die. The purge zone of the compression module includesan optional powder recovery system to recover excess powder from thefilters and return the powder to the dies.

[0121] In certain preferred embodiments of the invention, the core, orthe shell, or a portion thereof, is prepared by molding. In suchembodiments, the core, or the shell, or a portion thereof, is made froma flowable material. The flowable material may be any edible materialthat is flowable at a temperature between about 37° C. and 250° C., andthat is solid, semi-solid, or can form a gel at a temperature betweenabout −10° C. and about 35° C. When it is in the fluid or flowablestate, the flowable material may comprise a dissolved or moltencomponent, and optionally a solvent such as for example water or organicsolvents, or combinations thereof. The solvent may be partially orsubstantially removed by drying.

[0122] Suitable flowable materials for making the core, or the shell, ora portion thereof by molding include those comprising thermoplasticmaterials; film formers; thickeners such as gelling polymers orhydrocolloids; low melting hydrophobic materials such as fats and waxes;non-crystallizable carbohydrates; and the like. Suitable moltencomponents of the flowable material include thermoplastic materials, lowmelting hydrophobic materials, and the like. Suitable dissolvedcomponents for the flowable material include film formers, thickenerssuch as gelling polymers or hydrocolloids, non-crystallizablecarbohydrates, and the like.

[0123] Suitable thermoplastic materials can be molded and shaped whenheated, and include both water soluble and water insoluble polymers thatare generally linear, not crosslinked, nor strongly hydrogen bonded toadjacent polymer chains. Examples of suitable thermoplastic materialsinclude: thermoplastic water swellable cellulose derivatives,thermoplastic water insoluble cellulose derivatrives, thermoplasticvinyl polymers, thermoplastic starches, thermplastic polyalkaleneglycols, thermoplastic polyalkalene oxides, and amorphous sugar-glass,and the like, and derivatives, copolymers, and combinations thereof.Examples of suitable thermoplastic water swellable cellulose derivativesinclude hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose(HPMC), methyl cellulose (MC). Examples of suitable thermoplastic waterinsoluble cellulose derivatrives include cellulose acetate (CA), ethylcellulose (EC), cellulose acetate butyrate (CAB), cellulose propionate.Examples of suitable thermoplastic vinyl polymers include polyvinylalcohol (PVA) and polyvinyl pyrrolidone (PVP). Examples of suitablethermoplastic starches are disclosed for example in U.S. Pat. No.5,427,614. Examples of suitable thermoplastic polyalkalene glycolsinclude polyethylene glycol. Examples of suitable thermoplasticpolyalkalene oxides include polyethylene oxide having a molecular weightfrom about 100,000 to about 900,000 Daltons. Other suitablethermoplastic materials include sugar in the form on an amorphous glasssuch as that used to make hard candy forms.

[0124] Any film former known in the art is suitable for use in theflowable material of the present invention. Examples of suitable filmformers include, but are not limited to, film-forming water solublepolymers, film-forming proteins, film-forming water insoluble polymers,and film-forming pH-dependent polymers. In one embodiment, thefilm-former for making the core or shell or portion thereof by moldingmay be selected from cellulose acetate, ammonio methacrylate copolymertype B, shellac, hydroxypropylmethylcellulose, and polyethylene oxide,and combinations thereof.

[0125] Suitable film-forming water soluble polymers include watersoluble vinyl polymers such as polyvinylalcohol (PVA); water solublepolycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch,pullulan, methylethyl starch, carboxymethyl starch, pre-gelatinizedstarches, and film-forming modified starches; water swellable cellulosederivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose(HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose(HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); watersoluble copolymers such as methacrylic acid and methacrylate estercopolymers, polyvinyl alcohol and polyethylene glycol copolymers,polyethylene oxide and polyvinylpyrrolidone copolymers; and derivativesand combinations thereof.

[0126] Suitable film-forming proteins may be natural or chemicallymodified, and include gelatin, whey protein, myofibrillar proteins,coaggulatable proteins such as albumin, casein, caseinates and caseinisolates, soy protein and soy protein isolates, zein; and polymers,derivatives and mixtures thereof.

[0127] Suitable film-forming water insoluble polymers, include forexample ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers; and the like and derivatives,copolymers, and combinations thereof.

[0128] Suitable film-forming pH-dependent polymers include entericcellulose derivatives, such as for example hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate, celluloseacetate phthalate; natural resins, such as shellac and zein; entericacetate derivatives such as for example polyvinylacetate phthalate,cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; andenteric acrylate derivatives such as for example polymethacrylate-basedpolymers such as poly(methacrylic acid, methyl methacrylate) 1:2, whichis commercially available from Rohm Pharma GmbH under the tradename,EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, whichis commercially available from Rohm Pharma GmbH under the tradename,EUDRAGIT L, and the like, and derivatives, salts, copolymers, andcombinations thereof.

[0129] One suitable hydroxypropylmethylcellulose compound for use as athermoplastic film-forming water soluble polymer is “HPMC 2910”, whichis a cellulose ether having a degree of substitution of about 1.9 and ahydroxypropyl molar substitution of 0.23, and containing, based upon thetotal weight of the compound, from about 29% to about 30% methoxylgroups and from about 7% to about 12% hydroxylpropyl groups. HPMC 2910is commercially available from the Dow Chemical Company under thetradename METHOCEL E. METHOCEL E5, which is one grade of HPMC-2910suitable for use in the present invention, has a viscosity of about 4 to6 cps (4 to 6 millipascal-seconds) at 20° C. in a 2% aqueous solution asdetermined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which isanother grade of HPMC-2910 suitable for use in the present invention,has a viscosity of about 5 to 7 cps (5 to 7 millipascal-seconds) at 20°C. in a 2% aqueous solution as determined by a Ubbelohde viscometer.METHOCEL E15, which is another grade of HPMC-2910 suitable for use inthe present invention, has a viscosity of about 15000 cps (15millipascal-seconds) at 20° C. in a 2% aqueous solution as determined bya Ubbelohde viscometer. As used herein, “degree of substitution” shallmean the average number of substituent groups attached to aanhydroglucose ring, and “hydroxypropyl molar substitution” shall meanthe number of moles of hydroxypropyl per mole anhydroglucose.

[0130] One suitable polyvinyl alcohol and polyethylene glycol copolymeris commercially available from BASF Corporation under the tradenameKOLLICOAT IR.

[0131] As used herein, “modified starches” include starches that havebeen modified by crosslinking, chemically modified for improvedstability or optimized performance, or physically modified for improvedsolubility properties or optimized performance. Examples ofchemically-modified starches are well known in the art and typicallyinclude those starches that have been chemically treated to causereplacement of some of its hydroxyl groups with either ester or ethergroups. Crosslinking, as used herein, may occur in modified starcheswhen two hydroxyl groups on neighboring starch molecules are chemicallylinked. As used herein, “pre-gelatinized starches” or “instantizedstarches” refers to modified starches that have been pre-wetted, thendried to enhance their cold-water solubility. Suitable modified starchesare commercially available from several suppliers such as, for example,A. E. Staley Manufacturing Company, and National Starch & ChemicalCompany. One suitable film forming modified starch includes thepre-gelatinized waxy maize derivative starches that are commerciallyavailable from National Starch & Chemical Company under the tradenamesPURITY GUM and FILMSET, and derivatives, copolymers, and mixturesthereof Such waxy maize starches typically contain, based upon the totalweight of the starch, from about 0 percent to about 18 percent ofamylose and from about 100% to about 88% of amylopectin.

[0132] Another suitable film forming modified starch includes thehydroxypropylated starches, in which some of the hydroxyl groups of thestarch have been etherified with hydroxypropyl groups, usually viatreatment with propylene oxide. One example of a suitable hydroxypropylstarch that possesses film-forming properties is available from GrainProcessing Company under the tradename, PURE-COTE B790.

[0133] Suitable tapioca dextrins for use as film formers include thoseavailable from National Starch & Chemical Company under the tradenamesCRYSTAL GUM or K-4484, and derivatives thereof such as modified foodstarch derived from tapioca, which is available from National Starch andChemical under the tradename PURITY GUM 40, and copolymers and mixturesthereof.

[0134] Any thickener known in the art is suitable for use in theflowable material of the present invention. Examples of such thickenersinclude but are not limited to hydrocolloids (also referred to herein asgelling polymers), clays, gelling starches, and crystallizablecarbohydrates, and derivatives, copolymers and mixtures thereof.

[0135] Examples of suitable hydrocolloids (also referred to herein asgelling polymers) such as alginates, agar, guar gum, locust bean,carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan,maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gumarabic, inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan. Examples of suitable clays include smectitessuch as bentonite, kaolin, and laponite; magnesium trisilicate,magnesium aluminum silicate, and the like, and derivatives and mixturesthereof. Examples of suitable gelling starches include acid hydrolyzedstarches, and derivatives and mixtures thereof. Additional suitablethickening hydrocolloids include low-moisture polymer solutions such asmixtures of gelatin and other hydrocolloids at water contents up toabout 30%, such as for example those used to make “gummi” confectionforms.

[0136] Additional suitable thickeners include crystallizablecarbohydrates, and the like, and derivatives and combinations thereof.Suitable crystallizable carbohydrates include the monosaccharides andthe oligosaccharides. Of the monosaccharides, the aldohexoses e.g., theD and L isomers of allose, altrose, glucose, mannose, gulose, idose,galactose, talose, and the ketohexoses e.g., the D and L isomers offructose and sorbose along with their hydrogenated analogs: e.g.,glucitol (sorbitol), and mannitol are preferred. Of theoligosaccharides, the 1,2-disaccharides sucrose and trehalose, the1,4-disaccharides maltose, lactose, and cellobiose, and the1,6-disaccharides gentiobiose and melibiose, as well as thetrisaccharide raffinose are preferred along with the isomerized form ofsucrose known as isomaltulose and its hydrogenated analog isomalt. Otherhydrogenated forms of reducing disaccharides (such as maltose andlactose), for example, maltitol and lactitol are also preferred.Additionally, the hydrogenated forms of the aldopentoses: e.g., D and Lribose, arabinose, xylose, and lyxose and the hydrogenated forms of thealdotetroses: e.g., D and L erythrose and threose are preferred and areexemplified by xylitol and erythritol, respectively.

[0137] In one embodiment of the invention, the flowable materialcomprises gelatin as a gelling polymer. Gelatin is a natural,thermogelling polymer. It is a tasteless and colorless mixture ofderived proteins of the albuminous class which is ordinarily soluble inwarm water. Two types of gelatin—Type A and Type B—are commonly used.Type A gelatin is a derivative of acid-treated raw materials. Type Bgelatin is a derivative of alkali-treated raw materials. The moisturecontent of gelatin, as well as its Bloom strength, composition andoriginal gelatin processing conditions, determine its transitiontemperature between liquid and solid. Bloom is a standard measure of thestrength of a gelatin gel, and is roughly correlated with molecularweight. Bloom is defined as the weight in grams required to move ahalf-inch diameter plastic plunger 4 mm into a 6.67% gelatin gel thathas been held at 10° C. for 17 hours. In a preferred embodiment, theflowable material is an aqueous solution comprising 20% 275 Bloom porkskin gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60% water.

[0138] Suitable xanthan gums include those available from C. P. KelcoCompany under the tradenames KELTROL 1000, XANTROL 180, or K9B310.

[0139] Suitable clays include smectites such as bentonite, kaolin, andlaponite; magnesium trisilicate, magnesium aluminum silicate, and thelike, and derivatives and mixtures thereof.

[0140] “Acid-hydrolyzed starch,” as used herein, is one type of modifiedstarch that results from treating a starch suspension with dilute acidat a temperature below the gelatinization point of the starch. Duringthe acid hydrolysis, the granular form of the starch is maintained inthe starch suspension, and the hydrolysis reaction is ended byneutralization, filtration and drying once the desired degree ofhydrolysis is reached. As a result, the average molecular size of thestarch polymers is reduced. Acid-hydrolyzed starches (also known as“thin boiling starches”) tend to have a much lower hot viscosity thanthe same native starch as well as a strong tendency to gel when cooled.

[0141] “Gelling starches,” as used herein, include those starches that,when combined with water and heated to a temperature sufficient to forma solution, thereafter form a gel upon cooling to a temperature belowthe gelation point of the starch. Examples of gelling starches include,but are not limited to, acid hydrolyzed starches such as that availablefrom Grain Processing Corporation under the tradename PURE-SET B950;hydroxypropyl distarch phosphate such as that available from GrainProcessing Corporation under the tradename, PURE-GEL B990, and mixturesthereof.

[0142] Suitable low-melting hydrophobic materials include fats, fattyacid esters, phospholipids, and waxes. Examples of suitable fats includehydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil; and free fatty acids andtheir salts. Examples of suitable fatty acid esters include sucrosefatty acid esters, mono, di, and triglycerides, glyceryl behenate,glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate,glyceryl trilaurylate, glyceryl myristate, Glyco Wax-932, lauroylmacrogol-32 glycerides, and stearoyl macrogol-32 glycerides. Examples ofsuitable phospholipids include phosphotidyl choline, phosphotidylserene, phosphotidyl enositol, and phosphotidic acid. Examples ofsuitable waxes include carnauba wax, spermaceti wax, beeswax, candelillawax, shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate; and the like.

[0143] Suitable non-crystallizable carbohydrates includenon-crystallizable sugars such as polydextrose, and starch hydrolysates,e.g. glucose syrup, corn syrup, and high fructose corn syrup; andnon-crystallizable sugar-alcohols such as maltitol syrup.

[0144] Suitable solvents for optional use as components of the flowablematerial for making the core, or the shell, or a portion thereof bymolding include water; polar organic solvents such as methanol, ethanol,isopropanol, acetone, and the like; and non-polar organic solvents suchas methylene chloride, and the like; and mixtures thereof.

[0145] The flowable material for making the core or the shell or aportion thereof by molding may optionally comprise adjuvants orexcipients, which may comprise up to about 30% by weight of the flowablematerial. Examples of suitable adjuvants or excipients includeplasticizers, detackifiers, humectants, surfactants, anti-foamingagents, colorants, flavorants, sweeteners, opacifiers, and the like.Suitable plasticizers for making the core, the shell, or a portionthereof, by molding include, but not be limited to polyethylene glycol;propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate;dibutyl sebecate; vegetable oils such as castor oil, rape oil, oliveoil, and sesame oil; surfactants such as polysorbates, sodium laurylsulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol;diacetate of glycerol; triacetate of glycerol; natural gums; triacetin;acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate;diethylmalonate; dioctylphthalate; dibutylsuccinate;glyceroltributyrate; hydrogenated castor oil; fatty acids; substitutedtriglycerides and glycerides; and the like and/or mixtures thereof. Inone embodiment, the plasticizer is triethyl citrate. In certainembodiments, the shell is substantially free of plasticizers, i.e.contains less than about 1%, say less than about 0.01% of plasticizers.

[0146] In one preferred embodiment, the flowable material comprises lessthan 5% humectants, or alternately is substantially free of humectants,such as glycerin, sorbitol, maltitol, xylitol, or propylene glycol.Humectants have traditionally been included in pre-formed films employedin enrobing processes, such as that disclosed in U.S. Pat. Nos.5,146,730 and 5,459,983, assigned to Banner Gelatin Products Corp., inorder to ensure adequate flexibility or plasticity and bondability ofthe film during processing. Humectants function by binding water andretaining it in the film. Pre-formed films used in enrobing processescan typically comprise up to 45% water. Disadvantageously, the presenceof humectant prolongs the drying process, and can adversely affect thestability of the finished dosage form.

[0147] In certain embodiments, the core, the shell, or portions thereofmay be molded using a solvent-free process. In such embodiments, thecore may comprise active ingredient contained within an excipientmatrix. The matrix, or the core, or the shell, or portions thereoftypically comprises at least about 30 percent, e.g. at least about 45weight percent of a thermal-reversible carrier, and optionally up toabout 30 weight percent of various adjuvants such as for exampleplasticizers, gelling agents, strengthening agents, colorants,stabilizers, preservatives, and the like as known in the art. The matrixor the core, or the shell, or portions thereof may optionally furthercomprise up to about 55 weight percent of one or more release-modifyingmoldable excipients as described below.

[0148] The core may be in a variety of different shapes. For example,the core may be shaped as a polyhedron, such as a cube, pyramid, prism,or the like; or may have the geometry of a space figure with somenon-flat faces, such as a cone, truncated cone, cylinder, sphere, torus,or the like. In cetrain embodiments, the core has one or more majorfaces. For example in embodiments wherein the core is a compressedtablet, the core surface typically has two opposing major faces formedby contact with the upper and lower punch faces in the compressionmachine. In such embodiments the core surface typically furthercomprises a “belly-band” located between the two major faces, and formedby contact with the die walls in the compression machine. Exemplary coreshapes which may be employed include tablet shapes formed fromcompression tooling shapes described by “The Elizabeth Companies TabletDesign Training Manual” (Elizabeth Carbide Die Co., Inc., p. 7(McKeesport, Pa.) (incorporated herein by reference) as follows (thetablet shape corresponds inversely to the shape of the compressiontooling):  1. Shallow Concave.  2. Standard Concave.  3. Deep Concave. 4. Extra Deep Concave.  5. Modified Ball Concave.  6. Standard ConcaveBisect.  7. Standard Concave Double Bisect.  8. Standard ConcaveEuropean Bisect.  9. Standard Concave Partial Bisect. 10. Double Radius.11. Bevel & Concave. 12. Flat Plain. 13. Flat-Faced-Beveled Edge(F.F.B.E.). 14. F.F.B.E. Bisect. 15. F.F.B.E. Double Bisect. 16. Ring.17. Dimple. 18. Ellipse. 19. Oval. 20. Capsule. 21. Rectangle. 22.Square. 23. Triangle. 24. Hexagon. 25. Pentagon. 26. Octagon. 27.Diamond. 28. Arrowhead. 29. Bullet. 30. Shallow Concave. 31. StandardConcave. 32. Deep Concave. 33. Extra Deep Concave. 34. Modified BallConcave. 35. Standard Concave Bisect. 36. Standard Concave DoubleBisect. 37. Standard Concave European Bisect. 38. Standard ConcavePartial Bisect. 39. Double Radius. 40. Bevel & Concave. 41. Flat Plain.42. Flat-Faced-Beveled Edge (F.F.B.E.). 43. F.F.B.E. Bisect. 44.F.F.B.E. Double Bisect. 45. Ring. 46. Dimple. 47. Ellipse. 48. Oval. 49.Capsule. 50. Rectangle. 51. Square. 52. Triangle. 53. Hexagon. 54.Pentagon. 55. Octagon. 56. Diamond. 57. Arrowhead. 58. Bullet. 59.Barrel. 60. Half Moon. 61. Shield. 62. Heart. 63. Almond. 64. House/HomePlate. 65. Parallelogram. 66. Trapezoid. 67. FIG. 8/Bar Bell. 68. BowTie. 69. Uneven Triangle.

[0149] In one embodiment of the invention, the core comprises multipleportions, for example a first portion and a second portion. The portionsmay be prepared by the same or different methods and mated using varioustechniques, such as the thermal cycle molding and thermal settingmolding methods described herein. For example, the first and secondportions may both be made by compression, or both may be made bymolding. Or one portion may be made by compression and the other bymolding. The same or different active ingredient may be present in thefirst and second portions of the core. Alternately, one or more coreportions may be substantially free of active ingredients.

[0150] In certain embodiments of the invention, the core or a portionthereof may function to confer modified release properties to at leastone active ingredient contained therein. In such embodiments, whereinthe core or core portion is made by compression, as previously noted,the core preferably comprises a release-modifying compressibleexcipient. In such embodiments, wherein the core or core portion is madeby molding, as previously noted, the core preferably comprises arelease-modifying moldable excipient. In embodiments in which one ormore core portions function as an eroding matrix from which dispersedactive ingredient is liberated in a sustained, extended, prolonged, orretarded manner, the core portion preferably comprises arelease-modifying compressible or moldable excipient selected fromswellable erodible hydrophilic agents, pH-dependent polymers, andcombinations thereof.

[0151] In embodiments in which one or more core portions function as adiffusional matrix through which active ingredient is liberated in asustained, extended, prolonged, or retarded manner, the core portionpreferably comprises a release-modifying excipient selected fromcombinations of insoluble edible materials and pore formers.Alternately, in such embodiments in which the core portion is preparedby molding, the thermal-reversible carrier may function by dissolvingand forming pores or channels through which the active ingredient may beliberated.

[0152] The shell of the present invention comprises and first shellportion and a second shell portion that are compositionally different.For example the first and second shell portions may comprise differentingredients, or the first and second shell portions may comprisedifferent levels of the same ingredients, e.g. colorants, opacifiers,film-formers, etc. In one such embodiment, the first and second shellportions may be visually distinct from one another, for example thevisually distinct portions may be of different colors, hues, glosses,reflective qualities, brightness, depth, shades, chroma, opacity, etc.For example, the shell may have a red portion and a yellow portion, or aflat finish portion and a glossy portion, or an opaque portion and atranslucent portion. Alternatively, the first and second shell portionsmay have different thickness. The first and second shell portions mayhave different functionalities. For example, the first and second shellportions may confer different release properties to an active ingredientcontained in either the subject shell portion, or in a correspondingunderlying core portion. In one particular embodiment, the first shellportion may function as a diffusional membrane which contains poresthrough which fluids can enter the dosage form, and dissolved activeingredient can be released from an underlying core portion; and thesecond shell portion, may function as an eroding matrix from whichactive ingredient dispersed in the second shell portion is liberated bythe dissolution of successive layers of the shell portion surface.

[0153] The shell portions of the present invention may be prepared bymolding, using a solvent-free process, or a solvent-based process, anddepending on the method used, typically comprise a variety of excipientswhich are useful for conferring desired properties to the shellportions. The shell portions may optionally further comprise one or moreactive ingredients.

[0154] In embodiments in which the shell portion or portions areprepared using a solvent-free molding process, the shell will typicallycomprise at least about 30 percent, e.g. at least about 45 percent byweight of a thermal-reversible carrier. The shell portion or portionsmay optionally further comprise up to about 55 weight percent of arelease-modifying excipient. The shell portion or portions mayoptionally further comprise up to about 30 weight percent total ofvarious plasticizers, adjuvants and excipients. In certain embodimentsin which the shell portion is prepared by solvent-free molding, andfunctions to delay the release of one or more active ingredients from anunderlying core portion, the release modifying excipient is preferrablyselected from swellable, erodible hydrophilic materials.

[0155] In embodiments in which the shell portion or portions areprepared using a solvent-based molding process, the shell portion orportions will typically comprise at least about 10 weight percent, e.g.at least about 12 weight percent or at least about 15 weight percent orat least about 20 weight percent or at least about 25 weight percent ofa film-former. Here, the solvent-molded shell portion or portions mayoptionally further comprise up to about 55 weight percent of arelease-modifying excipient. The solvent-molded shell portion orportions may again also optionally further comprise up to about 30weight percent total of various plasticizers, adjuvants, and excipients.

[0156] In one embodiment of this invention, the shell portion orportions of the present invention, whether prepared by a solvent-freemolding process, or by a solvent-based molding process, aresubstantially free of pores having a diameter of 0.5-5.0 microns. Asused herein, “substantially free” means that the shell portion orportions have a pore volume of less than about 0.02 cc/g, preferablyless than about 0.01 cc/g, more preferably less than about 0.005 cc/g inthe pore diameter range of 0.5 to 5.0 microns. In contrast, typicalcompressed materials have pore volumes of more than about 0.02 cc/g inthis diameter range. In another embodiment of this invention, the coreis a molded core and the core or core portions are substantially free ofpores having a diameter of 0.5-5.0 microns.

[0157] The pore volume, pore diameter and density of the shell portionsof this invention may be determined using a Quantachrome InstrumentsPoreMaster 60 mercury intrusion porosimeter and associated computersoftware program known as “Porowin.” The procedure is documented in theQuantachrome Instruments PoreMaster Operation Manual. The PoreMasterdetermines both pore volume and pore diameter of a solid or powder byforced intrusion of a non-wetting liquid (mercury), which involvesevacuation of the sample in a sample cell (penetrometer), filling thecell with mercury to surround the sample with mercury, applying pressureto the sample cell by: (i) compressed air (up to 50 psi maximum); and(ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum).Intruded volume is measured by a change in the capacitance as mercurymoves from outside the sample into its pores under applied pressure. Thecorresponding pore size diameter (d) at which the intrusion takes placeis calculated directly from the so-called “Washburn Equation”:d=−(4γ(cos θ))/P where γ is the surface tension of liquid mercury, θ isthe contact angle between mercury and the sample surface and P is theapplied pressure.

[0158] Equipment used for pore volume measurements:

[0159] 1. Quantachrome Instruments PoreMaster 60.

[0160] 2. Analytical Balance capable of weighing to 0.0001 g.

[0161] 3. Desiccator.

[0162] Reagents used for measurements:

[0163] 1. High purity nitrogen.

[0164] 2. Triply distilled mercury.

[0165] 3. High pressure fluid (Dila AX, available from Shell ChemicalCo.).

[0166] 4. Liquid nitrogen (for Hg vapor cold trap).

[0167] 5. Isopropanol or methanol for cleaning sample cells.

[0168] 6. Liquid detergent for cell cleaning.

[0169] Procedure:

[0170] The samples remain in sealed packages or as received in thedessicator until analysis. The vacuum pump is switched on, the mercuryvapor cold trap is filled with liquid nitrogen, the compressed gassupply is regulated at 55 psi., and the instrument is turned on andallowed a warm up time of at least 30 minutes. The empty penetrometercell is assembled as described in the instrument manual and its weightis recorded. The cell is installed in the low pressure station and“evacuation and fill only” is selected from the analysis menu, and thefollowing settings are employed:

[0171] Fine Evacuation time: 1 min.

[0172] Fine Evacuation rate: 10

[0173] Coarse Evacuation time: 5 min.

[0174] The cell (filled with mercury) is then removed and weighed. Thecell is then emptied into the mercury reservoir, and two tablets fromeach sample are placed in the cell and the cell is reassembled. Theweight of the cell and sample are then recorded. The cell is theninstalled in the low-pressure station, the low-pressure option isselected from the menu, and the following parameters are set:

[0175] Mode: Low pressure

[0176] Fine evacuation rate: 10

[0177] Fine evacuation until: 200 μHg

[0178] Coarse evacuation time: 10 min.

[0179] Fill pressure: Contact +0.1

[0180] Maximum pressure: 50

[0181] Direction: Intrusion And Extrusion

[0182] Repeat: 0

[0183] Mercury contact angle; 140

[0184] Mercury surface tension: 480

[0185] Data acquisition is then begun. The pressure vs. cumulativevolume-intruded plot is displayed on the screen. After low-pressureanalysis is complete, the cell is removed from the low-pressure stationand reweighed. The space above the mercury is filled with hydraulic oil,and the cell is assembled and installed in the high-pressure cavity. Thefollowing settings are used:

[0186] Mode: Fixed rate

[0187] Motor speed: 5

[0188] Start pressure: 20

[0189] End pressure: 60,000

[0190] Direction: Intrusion and extrusion

[0191] Repeat: 0

[0192] Oil fill length: 5

[0193] Mercury contact angle: 140

[0194] Mercury surface tension: 480

[0195] Data acquisition is then begun and graphic plot pressure vs.intruded volume is displayed on the screen. After the high pressure runis complete, the low-and high-pressure data files of the same sample aremerged.

[0196] The shell portion or portions of the present invention, whetherprepared by a solvent-free molding process, or by a solvent-basedmolding process, typically has a surface gloss of at least about 150gloss units, e.g. at least about 175 gloss units, or at least about 190gloss units, when measured according to the method set forth below. Incontrast, typical sprayed coatings have gloss values of less than about150 gloss units. Dosage forms with high surface gloss are preferred byconsumers due to their aesthetic elegance and perceived swallowability.The surface gloss of the shell depends upon a number of factors,including the shell composition, the method of forming the shell, and,if a mold is used, the surface finish on the mold.

[0197] Shell or shell portions may be tested for surface gloss using aninstrument available from TriCor Systems Inc. (Elgin, Ill.) under thetradename TRI-COR MODEL 805A/806H SURFACE ANALYSIS SYSTEM and generallyin accordance with the procedure described in “TriCor Systems WGLOSS 3.4Model 805A/806H Surface Analysis System Reference Manual” (1996), whichis incorporated by reference herein, except as modified below.

[0198] This instrument uses a CCD camera detector, a flat diffuse lightsource, compares tablet samples to a reference standard, and determinesaverage gloss values at a 60 degree incident angle. During itsoperation, the instrument generates a gray-scale image, wherein theoccurrence of brighter pixels indicates the presence of more gloss atthat given location.

[0199] The instrument also incorporates software that uses a groupingmethod to quantify gloss: i.e., pixels with similar brightness which aregrouped together for averaging purposes.

[0200] The “percent full scale” or “percent ideal” setting (alsoreferred to as the “percent sample group” setting), is specified by theuser to designate the portion of the brightest pixels above thethreshold that will be considered as one group and averaged within thatgroup. “Threshold,” as used herein, is defined as the maximum glossvalue that will not be included in the average gloss value calculation.Thus, the background, or the non-glossy areas of a sample are excludedfrom the average gloss value calculations. The method disclosed in K.Fegley and C. Vesey, “The Effect of Tablet Shape on the Perception ofHigh Gloss Film Coating Systems,” which is available at www.colorcon.comas of Mar. 18, 2002 and incorporated by reference herein, is used tominimize the effects resulting from different tablet shapes, and toreport a metric that was comparable across the industry. (The 50% samplegroup setting is selected as the setting which best approximatesanalogous data from tablet surface roughness measurements.)

[0201] After initially calibrating the instrument using a calibrationreference plate (190-228; 294 degree standard; no mask, rotation 0,depth 0), a standard surface gloss measurement is created. For example,a standard surface gloss was obtained using gel-coated caplets availablefrom McNEIL-PPC, Inc. under the tradename, EXTRA STRENGTH TYLENOLGELCAPS. The average gloss value for a sample of 112 of such gel-coatedcaplets was then determined, while employing the 25 mm full view mask(190-280), and configuring the instrument to the following settings:

[0202] Rotation: 0

[0203] Depth: 0.25 inches

[0204] Gloss Threshold: 95

[0205] % Full Scale: 50%

[0206] Index of Refraction: 1.57

[0207] The average surface gloss value for the reference standard wasdetermined to be 269.

[0208] The total weight of the shell portion or portions is preferablyabout 20 percent to about 400 percent of the weight of the core. Inembodiments wherein the shell portion or portions prepared by asolvent-free molding process, the total weight of the shell portion orportions is typically from about 50 percent to about 400 percent, e.g.from about 75 percent to about 400 percent, or about 100 percent toabout 200 percent of the weight of the core. In embodiments wherein theshell portion or portions are prepared by a solvent-based moldingprocess, the total weight of the shell portion or portions is typicallyfrom about 20 percent to about 100 percent of the weight of the core.

[0209] Typical shell portion thicknesses which may be employed in thisinvention are about 50 to about 4000 microns. In certain preferredembodiments, the shell has a thickness of less than 800 microns. Inembodiments wherein the shell portion is prepared by a solvent-freemolding process, the shell portion typically has a thickness of about500 to about 4000 microns, e.g. about 500 to about 2000 microns, sayabout 500 to about 800 microns, or about 800 to about 1200 microns. Inembodiments wherein the shell portion is prepared by a solvent-basedmolding process, the shell portion typically has a thickness of lessthan about 800 microns, e.g. about 100 to about 600 microns, say about150 to about 400 microns. In a particularly preferred embodiment thedosage form comprises first and second core portions and first andsecond shell portions, and at least one of the shell portions has athickness of less than about 800 microns, e.g. about 100 to about 600microns, e.g. about 150 to about 400 microns

[0210] Suitable thermal-reversible carriers for making the core, or theshell, or a portion thereof, by molding are thermoplastic materialstypically having a melting point below about 110° C., more preferablybetween about 20 and about 100° C. Examples of suitablethermal-reversible carriers for solvent-free molding includethermplastic polyalkalene glycols, thermoplastic polyalkalene oxides,low melting hydrophobic materials, thermoplastic polymers, thermoplasticstarches, and the like. Preferred thermal-reversible carriers includepolyethylene glycol and polyethylene oxide. Suitable thermoplasticpolyalkylene glycols for use as thermal-reversible carriers includepolyethylene glycol having molecular weight from about 100 to about20,000, e.g. from about 100 to about 8,000 Daltons. Suitablethermoplastic polyalkalene oxides include polyethylene oxide having amolecular weight from about 100,000 to about 900,000 Daltons. Suitablelow-melting hydrophobic materials for use as thermal-reversible carriersinclude fats, fatty acid esters, phospholipids, and waxes which aresolid at room temperature, fat-containing mixtures such as chocolate;and the like. Examples of suitable fats include hydrogenated vegetableoils such as for example cocoa butter, hydrogenated palm kernel oil,hydrogenated cottonseed oil, hydrogenated sunflower oil, andhydrogenated soybean oil; and free fatty acids and their salts. Examplesof suitable fatty acid esters include sucrose fatty acid esters, mono,di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,glyceryl myristate, Glyco Wax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides. Examples of suitable phospholipidsinclude phosphotidyl choline, phosphotidyl serene, phosphotidylenositol, and phosphotidic acid. Examples of suitable waxes which aresolid at room temperature include carnauba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax.Suitable thermoplastic polymers for use as thermal-reversible carriersinclude thermoplastic water swellable cellulose derivatives,thermoplastic water insoluble polymers, thermoplastic vinyl polymers,thermoplastic starches, and thermoplastic resins, and combinationsthereof. Suitable thermoplastic water swellable cellulose derivativesinclude include hydroxypropylmethyl cellulose (HPMC), methyl cellulose(MC), carboxymethylcellulose (CMC), cross-linked hydroxypropylcellulose,hydroxypropyl cellulose (HPC), hydroxybutylcellulose (HBC),hydroxyethylcellulose (HEC), hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose, and salts,derivatives, copolymers, and combinations thereof. Suitablethermoplastic water insoluble polymers include ethylcellulose, polyvinylalcohols, polyvinyl acetate, polycaprolactones, cellulose acetate andits derivatives, acrylates, methacrylates, acrylic acid copolymers, andthe like and derivatives, copolymers, and combinations thereof. Suitablethermoplastic vinyl polymers include polyvinylacetate, polyvinylalcohol, and polyvinyl pyrrolidone (PVP). Examples of suitablethermoplastic starches for use as thermal-reversible carriers aredisclosed for example in U.S. Pat. No. 5,427,614. ______. Examples ofsuitable thermoplastic resins for use as themal-reversible carriersinclude dammars, mastic, rosin, shellac, sandarac, and glcerol ester ofrosin. In one embodiment, the thermal-reversible carrier for making thecore, or a portion thereof, by molding is selected from polyalkyleneglycols, polyalkaline oxides, and combinations thereof.

[0211] Suitable release-modifying excipients for making the core, or theshell, or a portion thereof, by solvent free or solvent based moldinginclude but are not limited to swellable erodible hydrophilic materials,pH-dependent polymers, pore formers, and insoluble edible materials. Inone embodiment, suitable release-modifying excipients for making thecore, or the shell, or a portion thereof, by molding includehydroxypropylmethylcellulose, polyethylene oxide, ammonio methacrylatecopolymer type B, and shellac, and combinations thereof.

[0212] Suitable swellable erodible hydrophilic materials for use asrelease-modifying excipients for making the core, or the shell, or aportion thereof by a solvent-free molding process include waterswellable cellulose derivatives, polyalkalene glycols, thermoplasticpolyalkalene oxides, acrylic polymers, hydrocolloids, clays, gellingstarches, and swelling cross-linked polymers, and derivitives,copolymers, and combinations thereof. Examples of suitable waterswellable cellulose derivatives include sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples ofsuitable polyalkalene glyclols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkalene oxides include poly (ethyleneoxide). Examples of suitable acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, CARBOPOL(high-molceular weight cross-linked acrylic acid homopolymers andcopolymers), and the like. Examples of suitable hydrocolloids includealginates, agar, guar gum, locust bean gum, kappa carrageenan, iotacarrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellangum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan,chitin, cyclodextrin, chitosan. Examples of suitable clays includesmectites such as bentonite, kaolin, and laponite; magnesiumtrisilicate, magnesium aluminum silicate, and the like, and derivativesand mixtures thereof. Examples of suitable gelling starches include acidhydrolyzed starches, swelling starches such as sodium starch glycolate,and derivatives thereof. Examples of suitable swelling cross-linkedpolymers include cross-linked polyvinyl pyrrolidone, cross-linked agar,and cross-linked carboxymethylcellose sodium.

[0213] Suitable pH-dependent polymers for use as release-modifyingmoldable excipients for making the molded matrix or molded core ormolded shell or a portion thereof by molding include enteric cellulosederivatives, for example hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, cellulose acetatephthalate; natural resins such as shellac and zein; enteric acetatederivatives such as for example polyvinylacetate phthalate, celluloseacetate phthalate, acetaldehyde dimethylcellulose acetate; and entericacrylate derivatives such as for example polymethacrylate-based polymerssuch as poly(methacrylic acid, methyl methacrylate) 1:2, which iscommercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1, whichis commercially available from Rohm Pharma GmbH under the tradenameEUDRAGIT L, and the like, and derivatives, salts, copolymers, andcombinations thereof.

[0214] Suitable insoluble edible materials for use as release-modifyingexcipients making the core, or the shell, or a portion thereof bymolding, include water-insoluble polymers, and low-melting hydrophobicmaterials. Examples of suitable water-insoluble polymers includeethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers; and the like and derivatives,copolymers, and combinations thereof. Suitable low-melting hydrophobicmaterials include fats, fatty acid esters, phospholipids, and waxes.Examples of suitable fats include hydrogenated vegetable oils such asfor example cocoa butter, hydrogenated palm kernel oil, hydrogenatedcottonseed oil, hydrogenated sunflower oil, and hydrogenated soybeanoil; and free fatty acids and their salts. Examples of suitable fattyacid esters include sucrose fatty acid esters, mono, di, andtriglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, Glyco Wax-932, lauroyl macrogol-32 glycerides, and stearoylmacrogol-32 glycerides. Examples of suitable phospholipids includephosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, andphosphotidic acid. Examples of suitable waxes include carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate; andthe like.

[0215] Suitable pore formers for use as release-modifying excipients formaking the molded matrix, the core, the shell, or a portion thereof bymolding include water-soluble organic and inorganic materials. In oneembodiment the pore former is hydroxypropylmethylcellulose. Examples ofsuitable water-soluble organic materials include water soluble polymersincluding water soluble cellulose derivatives such ashydroxypropylmethylcellulose, and hydroxypropylcellulose; water solublecarbohydrates such as sugars, and starches; water soluble polymers suchas polyvinylpyrrolidone and polyethylene glycol, and insoluble swellingpolymers such as microcrystalline cellulose. Examples of suitable watersoluble inorganic materials include salts such as sodium chloride andpotassium chloride and the like and/or mixtures thereof.

[0216] In embodiments in which the first or second shell portioncomprises an active ingredient intended to have immediate release fromthe dosage form, the shell portion is preferably prepared via thesolvent-free molding method described above. In such embodiments thethermal-reversible carrier is preferably selected from polyethyleneglycol with weight average molecular weight from about 1450 to about20000, polyethylene oxide with weight average molecular weight fromabout 100,000 to about 900,000, and the like.

[0217] In embodiments in which at least one of the first or second shellportions function to confer modified release properties to at least oneactive ingredient contained within the dosage form, in the core, theshell or both, the shell portion typically comprises at least onerelease modifying agent as described above.

[0218] In embodiments of the invention in which the core portions andshell portions each comprise a dose of active ingredient, the dosageform may function for example as a multi-compartment, e.g. afour-compartment pulsatile release delivery system. In one suchembodiment, each of the compartments may comprise a dose of the sameactive ingredient, to be release at a desired time or rate. In anothersuch embodiment, the corresponding first core portion and first shellportions may comprise a dose of the same first active ingredient to bereleased at a desired time or rate, while the second core portion andsecond shell portion may comprise a dose of the same second activeingredient to be released at a desired time or rate. In suchembodiments, each compartment comprises inactive materials which enablethe desired functionality of that particular core portion or shellportion.

[0219] In certain such embodiments, the dosage form may further comprisea water-impermeable barrier layer between the first and second coreportions. The water-impermeable barrier layer may be made by any method,for example compression or molding, and preferably comprises at leastone water-insoluble material selected from water-insoluble polymers,insoluble edible materials, pH-dependent polymers, and mixtures thereof.

[0220] In one particular embodiment of this invention, at least oneactive ingredient contained within the dosage form exhibits a delayedburst release profile. By “delayed burst release profile” it is meantthat the release of that particular active ingredient from the dosageform is delayed for a pre-determined time after ingestion by thepatient, and the delay period (“lag time”) is followed by prompt(immediate) release of that active ingredient. At least one shellportion of the present invention provides for the delay period and ispreferraby substantially free of the active ingredient to be released ina delayed burst manner. In such embodiments, the delayed burst activeingredient is typically contained within the corresponding underlyingcore portion. In these embodiments, the core portion may be prepared bycompression or molding, and is formulated for immediate release, as isknown in the art, so that the core portion is readily soluble uponcontact with the dissolution medium. In such embodiments the coreportion preferably comprises a disintegrant, and optionally comprisesadditional excipients such as fillers or thermoplastic materialsselected from water-soluble or low-melting materials, and surfactants orwetting agents. In these embodiments, the dissolution of the burstrelease active ingredient, after the delay period, meets USPspecifications for immediate release tablets containing that activeingredient. For example, for acetaminophen tablets, USP 24 specifiesthat in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50rpm, at least 80% of the acetaminophen contained in the dosage form isreleased therefrom within 30 minutes after dosing, and for ibuprofentablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USPapparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofen containedin the dosage form is released therefrom within 60 minutes after dosing.See USP 24, 2000 Version, 19-20 and 856 (1999).

[0221] In another particular embodiment of this invention at least oneactive ingredient contained within the dosage form exhibits a delayedand sustained release profile. By “delayed then sustained releaseprofile” it is meant that the release of that particular activeingredient from the dosage form is delayed for a pre-determined timeafter ingestion by the patient, and the delay period (“lag time”) isfollowed by sustained (prolonged, extended, or retarded) release of thatactive ingredient. At least one shell portion of the present inventionprovides for the delay period, and is preferraby substantially free ofthe active ingredient to be released in a delayed then sustained manner.In such embodiments, the delayed then sustained release activeingredient is preferrably contained within the corresponding underlyingcore portion. In such embodiments the core portion may function forexample as an eroding matrix or a diffusional matrix, or an osmoticpump. In embodiments in which the core portion functions as adiffusional matrix through which active ingredient is liberated in asustained, extended, prolonged, or retarded manner, the core portionpreferably comprises a release-modifying excipient selected fromcombinations of insoluble edible materials and pore-formers.Alternately, in such embodiments in which the core portion is preparedby molding, the thermal-reversible carrier may function by dissolvingand forming pores or channels through which the active ingredient may beliberated. In embodiments in which the core portion functions as aneroding matrix from which dispersed active ingredient is liberated in asustained, extended, prolonged, or retarded manner, the core portionpreferably comprises a release-modifying compressible or moldableexcipient selected from swellable erodible hydrophilic materials,pH-dependent polymers, and combinations thereof.

[0222] In embodiments in which one or more core portions function as adiffusional matrix through which active ingredient contained therein isliberated in a sustained, extended, prolonged, or retarded manner, thecore portion preferably comprises a release-modifying excipient selectedfrom combinations of insoluble edible materials and pore formers.Alternately, in such embodiments in which the core portion is preparedby solven-free molding, the thermal-reversible carrier may function bydissolving and forming pores or channels through which the activeingredient may be liberated.

[0223] In embodiments in which the core or a portion thereof functionsas an eroding matrix from which dispersed active ingredient is liberatedin a sustained, extended, prolonged, or retarded manner, the coreportion preferably comprises a release-modifying compressible ormoldable excipient selected from swellable erodible hydrophilicmaterials, pH-dependent polymers, insoluble edible materials, andcombinations thereof. In such embodiments, the overlaying shell portionwill typically be breached or dissolved prior to onset of erosion of theunderlying core portion, and release of active ingredient therefrom.

[0224] In embodiments in which a shell portion functions by anerosion-based mechanism to provide a time delay for the release of anactive ingredient from an underlying core portion, the release-delayingshell portion preferably comprises a release modifying excipientselected from swellable erodible hydrophilic materials, insoluble ediblematerials, and combinations thereof.

[0225] In embodiments in which a shell portion functions as an erodingmatrix from which active ingredient dispersed therein is liberated in asustained, extended, prolonged, or retarded manner, the shell portionpreferably comprises a release-modifying compressible or moldableexcipient selected from swellable erodible hydrophilic materials,pH-dependent polymers, insoluble edible materials, and combinationsthereof.

[0226] In embodiments of the invention, in which a shell portionfunctions to confer a delay to the release of one or more activeingredients contained in an underlying core portion, therelease-delaying shell portion preferably provides a delay of greaterthan one hour, for example at least about 3 hours, or at least about 4hours, or at least about 6 hours, or at least about 12 hours to theonset of dissolution of the active ingredient upon contacting of thedosage form with a liquid medium such as water, gastrointestinal fluidor the like. The delay period is typically controlled by the shellportion thickness, composition, or a combination thereof. In oneembodiment the delay period is independent of the pH of the dissolutionmedia or fluid environment. For example, the average lag-time fordissolution of active ingredient in 0.1 N HCl is not substantiallydifferent (i.e. within about 30 minutes, preferably within about 15minutes) from the average lag-time for the dissolution of activeingredient in pH 5.6 buffer system. In certain such embodiments, therelease-delaying shell portion prefarably comprises a release modifyingexcipient selected from swellable erodible hydrophilic materials,insoluble edible materials, and combinations thereof.

[0227] In embodiments in which one or more shell portions contain activeingredient which is released essentially immediately upon ingestion ofthe dosage form, the shell portion preferably comprises materials whichexhibit rapid dissolution in gastro-intestinal fluids. For example theimmediate release shell portion or portions may comprise readily solublematerials selected from water soluble or water swellable thermoplasticfilm formers, water soluble or water swellable thickeners,crystallizable and non-crystallizable carbohydrates. In certain suchembodiments, suitable water soluble or water swellable thermoplasticfilm formers may be selected from water swellable cellulose derivatives,thermoplastic starches, polyalkalene glycols, polyalkalene oxides, andamorphous sugar glass, and combinations thereof. In certain other suchembodiments, suitable film formers may be selected from film formingwater soluble polymers such as for example water soluble vinyl polymers,water soluble polycarbohydrates, water swellable cellulose derivatives,and water soluble copolymers; film-forming proteins, and combinationsthereof. In certain other such embodiments, suitable thickeners may beselected from gelling polymers or hydrocolloids; gelling starches, andcrystallizable carbohydrates. In certain other such embodiments,suitable non-crystallizable carbohydrates may be selected frompolydextrose, starch hydrolysates, and non-crystallizable sugaralcohols. In such embodiments, the immediate release shell portion willpreferably be breached or dissolved within 30 minutes in 900 ml water or0.1 N HCl, or phosphate buffer solution at 37° C. with stirring by a USPtype 2 (Paddle method) at 50 or 100 rpm.

[0228] In one embodiment of the invention, the shell portion or portionsadditionally comprise at least one active ingredient which may be thesame or different than the active ingredient contained in the core.

[0229] In embodiments in which the first or second shell portions confersustained, extended, or retarded release of an active ingredientcontained in an underlying core or core portion, the release-modifyingagent in said shell portion preferably comprises a pore-former, andoptionally a film-former. In a particularly preferred embodiment, theshell portion functions as a diffusional membrane. In some suchembodiments, the dissolution of the active ingredient may follow“diffusion-controlled” release kinetics, as described for example inExample 1 of U.S. Pat. No. 5,286,497. Shell portions which confersustained, extended, or retarded release and/or function as diffusionalmembranes can be prepared by a solvent-free method, or a solvent-basedmethod, as described above.

[0230] In embodiments in which the first or second shell portions confersustained, extended, or retarded release of an active ingredientcontained in said first or second shell portion, the release-modifyingagent in said shell portion preferably comprises a swellable erodiblehydrophilic material, and may optionally comprise a secondary gellingagent such as for example cross-linked carboxymethylcellulose,cross-linked polyvinylpyrrolidone, or sodium starch glycolate.

[0231] In embodiments in which the first or second shell portions confera delayed release to an active ingredient contained in an underlyingcore or core portion, the release-modifying agent is preferably selectedfrom swellable erodible hydrophilic materials. Shell portions whichconfer delayed release can be prepared by a solvent-free method, or asolvent-based method, as described above.

[0232] In embodiments in which the first or second shell portionsprovide a barrier to prevent release therethrough of an activeingredient contained in the underlying core or core portion, the shellportion is preferably prepared via a solvent-free molding method, asdescribed above. In such embodiments, the thermal-reversible carrier ispreferably selected from waxes, such as for example camuba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; hydrogenated vegetable oils such as for examplecocoa butter, hydrogenated castor oil; other waxy materials such as forexample glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate; thermal-reversible polymers such as for examplepolycaprolactones and polyvinyl acetate. In certain embodiments, animpermeable barrier can be formed which consists essentially of thethermal reversible carrier. In such embodiments, an additionalrelease-modifying agent is not necessary. In certain other embodiments,the release-modifying agent is preferably selected from water insolublepolymers such as cellulose acetate, acrylates, acrylic acid copolymers,cellulose acetate, cellulose acetate propionate, cellulose acetatepropionate, cellulose propionate, cellulose acetate butyrate, celluloseacetate phthalate, acetaldehyde dimethylcellulose acetate, celluloseacetate ethyl carbamate, cellulose acetate methyl carbamate, celluloseacetate diethyl aminoacetate, ethylcellulose, methacrylates, polyvinylalcohols, polyvinyl acetate, polycaprolactones, and the like, andmixtures thereof. In such embodiments, the shell portion may optionallyfurther comprise a liquid carrier such as for example mineral oil,propylene glycol, low molecular weight polyethylene glycol, glycerin,and the like.

[0233] In one embodiment of the invention, the core, the shell, a coreportion, or a shell portion is made by the thermal setting moldingmethod and apparatus described in copending U.S. patent application Ser.No. 09/966,450, pages 57-63, the disclosure of which is incorporatedherein by reference. In this embodiment, the core, the shell, or aportion thereof is formed by injecting a starting material in flowableform into a molding chamber. The starting material preferably comprisesan active ingredient and a thermal setting material at a temperatureabove the melting point of the thermal setting material but below thedecomposition temperature of the active ingredient. The startingmaterial is cooled and solidifies in the molding chamber into a shapedform (i.e., having the shape of the mold).

[0234] According to this method, the starting material must be inflowable form. For example, it may comprise solid particles suspended ina molten matrix, for example a polymer matrix. The starting material maybe completely molten or in the form of a paste. The starting materialmay comprise an active ingredient dissolved in a molten material.Alternatively, the starting material may be made by dissolving a solidin a solvent, which solvent is then evaporated from the startingmaterial after it has been molded.

[0235] The starting material may comprise any edible material which isdesirable to incorporate into a shaped form, including activeingredients, nutritionals, vitamins, minerals, flavors, sweeteners, andthe like. Preferably, the starting material comprises an activeingredient and a thermal setting material. The thermal setting materialmay be any edible material that is flowable at a temperature betweenabout 37 and about 120° C., and that is a solid at a temperature betweenabout 0 and about 35° C. Preferred thermal setting materials includewater-soluble polymers such as polyalkylene glycols, polyethylene oxidesand derivatives, and sucrose esters; fats such as cocoa butter,hydrogenated vegetable oil such as palm kernel oil, cottonseed oil,sunflower oil, and soybean oil; mono-, di-, and triglycerides,phospholipids, waxes such as camuba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax;fat-containing mixtures such as chocolate; sugar in the form on anamorphous glass such as that used to make hard candy forms, sugar in asupersaturated solution such as that used to make fondant forms;low-moisture polymer solutions such as mixtures of gelatin and otherhydrocolloids at water contents up to about 30% such as those used tomake “gummi” confection forms. In a particularly preferred embodiment,the thermal setting material is a water-soluble polymer such aspolyethylene glycol.

[0236] In another embodiment of the invention, the core, the shell, acore portion, or a shell portion is make using the thermal cycle moldingmethod and apparatus described in copending U.S. patent application Ser.No. 09/966,497, pages 27-51, the disclosure of which is alsoincorporated herein by reference. In the thermal cycle molding methodand apparatus of U.S. patent application Ser. No. 09/966,497, a thermalcycle molding module having the general configuration shown in FIG. 3therein is employed. The thermal cycle molding module 200 comprises arotor 202 around which a plurality of mold units 204 are disposed. Thethermal cycle molding module includes a reservoir 206 (see FIG. 4) forholding flowable material to make the core, the shell, a core portion,or a shell portioncore. In addition, the thermal cycle molding module isprovided with a temperature control system for rapidly heating andcooling the mold units. FIGS. 55 and 56 depict such a temperaturecontrol system 600.

[0237] This invention will be illustrated by the following examples,which are not meant to limit the invention in any way.

EXAMPLE 1

[0238] Dosage forms according to the invention comprising a core withina shell comprising a first shell portion and a second shell portion wereprepared as follows.

[0239] The following ingredients were used to make the cores: Mg/dosageIngredient Trade Name Manufacturer Weight % Form Verapamil HCL ExtendedVerelan PM 300 mg Schwarz Pharma, Inc., 22.0 131 Release Pelletscapsules Gainesville, GA Polyethylene Glycol 3350 Carbowax ® UnionCarbide 47.0 279 Corporation, Danbury, CT Shellac PowderMantrose-Haeuser 10.0 59 Company, Atteboro, MA Croscarmellose SodiumAc-Di-Sol ® FMC Corporation, 21.0 125 Newark, DE

[0240] The cores were prepared as follows: a beaker was submersed in a70° C. water bath (Ret digi-visc; Antal-Direct, Wayne, Pa.). Thepolyethylene glycol (PEG) was added to the beaker and mixed with aspatula until melted. The shellac powder was screened through a #40 meshscreen, and then added to the molten PEG. The combined ingredients weremixed until all the powder was dispersed. Croscarmellose sodium wasadded next and the beaker contents were mixed for an additional twominutes. The verapamil HCL pellets were then added, and the contentswere mixed for five more minutes. Cores were made by dispensing 620 to640 mg of the resulting molten mixture into an open stainless steel mold(round, 0.4455 inch diameter) and closing the mold. The finished coreswere ejected from the mold.

[0241] The first shell portion was made using the following ingredients:Mg/Dosage Ingredient Trade Name Manufacturer Weight % FormPseudoephedrine HCl Crystal BASF 30.0 53 PharmaChemikalien GmbH & Co.Ludwigshafen/Rhein. Polyethylene Glycol 3350 Carbowax ® Union Carbide50.0 89 Corporation, Danbury, CT Polyethylene Oxide (MW Polyox ® WSRN-80 Union Carbide 15.0 27 200,000) Corporation, Danbury, CT TriethylCitrate Morflex, Inc., 5.0 9 Greensboro, NC

[0242] The first shell portion material was prepared by first submersinga beaker in a 70° C. water bath (Ret digi-visc; Antal-Direct, Wayne,Pa.). The polyethylene glycol (PEG) was added to the beaker and mixedwith a spatula until melted. The triethyl citrate was then added to themolten PEG and the mixture was mixed for one minute. The polyethyleneoxide (PEO) was added thereto, and the ingredients were mixed for 10additional minutes. The pseudoephedrine hydrochloride was added, and theingredients were mixed for two more minutes. The first shell portionmaterial was provided in flowable form.

[0243] The second shell portion was made using the followingingredients: Mg/Dosage Ingredient Trade Name Manufacturer Weight % FormDextromethorphan HBr Roche Chemical 10.0 16 Co., Belvidere, NJPolyethylene Glycol 3350 Carbowax ® Union Carbide 50.0 77 Corporation,Danbury, CT Polyethylene Oxide (MW Polyox ® WSR N-80 Union Carbide 15.023 200,000) Corporation, Danbury, CT Shellac Powder Mantrose-Haeuser10.0 16 Company, Atteboro, MA Croscarmellose Sodium Ac-Di-Sol ® FMCCorporation, 5.0 8 Newark, DE Triethyl Citrate Morflex, Inc., 10.0 16Greensboro, NC

[0244] The second shell portion material was prepared by firstsubmersing a beaker in a 70° C. water bath (Ret digi-visc; Antal-Direct,Wayne, Pa.). PEG was added to the beaker and mixed with a spatula untilmelted. The shellac powder was screened through a #40 mesh screen, andthen added to the molten PEG. The combined ingredients were mixed untilall powder was dispersed. The triethyl citrate was added next and thebeaker contents were mixed for one minute. PEO was added to the beakerand the mixture was mixed for 10 minutes. Croscarmellose sodium was thenadded and the contents of the beaker were mixed for two additionalminutes. Finally, dextromethorphan HBr was added to the beaker and theingredients were mixed for two more minutes. The second shell portionmaterial was provided in flowable form.

[0245] A laboratory scale thermal cycle molding unit was used to applythe first and second shell portions to the cores, and comprised a singlemold assembly made from an upper mold assembly portion comprising anupper mold cavity, and a lower mold assembly portion comprising a lowermold cavity. The lower mold assembly portion was first cycled to a hotstage at 85° C. for 30 seconds. The first shell portion material ofExample 1 was introduced into the lower mold cavity. A core prepared asdescribed above was then inserted into the cavity. A blank upper moldassembly portion was mated with the lower mold assembly portion. Themold assembly was then cycled to a cold stage at 5° C. for 60 seconds toharden the first shell portion. The blank mold assembly portion wasremoved from the lower mold assembly portion, and the half-coated corewas ejected from the lower mold cavity. The “weight gain” due to thefirst shell portion (i.e. the difference in weight between thehalf-coated core and the uncoated core) was recorded.

[0246] The upper mold assembly portion was cycled to a hot stage at 85°C. for 30 seconds. The second shell portion material was added to theupper mold cavity. The half-coated core was then inserted into the uppermold cavity such that the uncoated portion of the core rested within theupper mold cavity. The lower mold assembly portion, which had beenmaintained at 5° C., was then mated with the upper mold assemblyportion. The upper mold assembly portion was then cycled to a cold stageat 5° C. for 60 seconds to harden the second shell portion. The lowermold assembly portion was then removed and the finished dosage form, amolded core coated with two different shell portions, was ejected fromthe upper mold cavity. The weight gain due to the second shell portion(i.e. the difference in weight between the finished dosage form, and thehalf-coated core) was recorded.

[0247] The release profiles for the three active ingredients containedin the dosage form of Example 1 were compared with those of other dosageforms containing the same active ingredients. The results are shown inFIG. 3, which depicts the percent release of active ingredient versushours for the dosage form of Example 1 and the other dosage forms. Curve(a) depicts the dissolution profile of the verapamil HCL contained inthe core of the dosage form of this example. Curve (b) depicts thedissolution of verapamil from commercially available, sustained releasecapsules (Verelan® PM 300 mg). Curve (c) shows the dissolution ofdextromethorphan HBr contained in the second shell portion of the dosageform of this example. Curve (d) shows the dissolution profile ofpseudoephedrine HCl contained in the first shell portion of the dosageform of this example. Curve (e) depicts the dissolution profile ofpseudoephedrine HCl from commercially available immediate releasetablets (Sudafed®). Curve (f) depicts the dissolution profile ofdextromethorphan HBr from commercially available immediate releasecoated tablets (Tylenol® Cold caplets).

[0248] All curves were derived using the following dissolutionapparatus: USP Type II apparatus (paddles, 50 RPM). Media: pH 7.2phosphate buffer at 37° C. Time points: Samples were removed at 0.5, 1,2, 4, 8, 12, 16, 20, and 24 hours to be analyzed for pseudoephedrineHCl, dextromethorphan HBr, and verapamil HCl. Dissolution samples wereanalyzed for these three active ingredients versus a standard preparedat the theoretical concentration for 100% released of each compound.Samples were analyzed using an HPLC equipped with a Waters® 717Autoinjector and a Waters® 486 UV detector set at a wavelength of 214nm. The mobile phase was prepared using 55% acetonitrile and 45% 18 mMPotassium phosphate buffer. The injection volume was 50 μL with a runtime of approximately 8 minutes an a pump flow of 2.0 mL/min. A Zorbax®300-SCX (4.6 m×25 cm) column was used.

[0249] The curves depicted in FIG. 3 demonstrate that the verapamil HClwas released from the dosage form of the present example in a sustainedmanner. The dextromethorphan HBr was released from the dosage form ofthe present example in a delayed manner. The pseudoephedrine HCl wasimmediately released from the dosage form of the present example.

EXAMPLE 2

[0250] Dosage forms according to the invention comprising a core havinga first core portion and a second core portion within a shell having afirst shell portion and a second shell portion were prepared as follows.

[0251] The following ingredients were used to make the first coreportion: Mg/Dosage Ingredient Trade Name Manufacturer Weight % FormPseudoephedrine HCl Crystal BASF 15.0 48 PharmaChemikalien GmbH & Co.Ludwigshafen/Rhein. Polyethylene Oxide Polyox ® WSR N-750 Union Carbide75.0 239 (MW 300,000) Corporation, Danbury, CT Hydroxypropyl Methocel E5Dow Chemical 8.5 27 Methylcellulose Company, Midland, MI MagnesiumStearate Mallinckrodt Inc., 1.5 5 St. Louis, MO Alcohol USP (dried assolvent)

[0252] The pseudoephedrine HCl crystal, hydroxypropyl methylcellulose,and PEO (MW=300,000), were first mixed in a plastic bag for 1-2 minutes.This powder mixture was added into the (5 qt) bowl of a planetary mixer(Hobart Corp., Dayton, Ohio). The alcohol was added to the powdermixture while mixing at low speed. The ingredients were mixed for 10minutes. The resulting granulation was removed from the bowl and driedat room temperature for 12 to 16 hours to remove all residual solvent.The granulation was screened through a #20 mesh screen and were put intoa plastic bag. Magnesium stearate was added to the dry granules,followed by mixing for 3 minutes to form the first core portion.

[0253] The following ingredients were used to make the second coreportion: Mg/Dosage Ingredient Trade Name Manufacturer Weight % FormDextromethorphan HBr Roche Chemical Co. 15.1 48 Belvidere, NJPolyethylene Oxide Polyox ® WSR N-750 Union Carbide 75.4 240 (MW300,000) Corporation, Danbury, CT Hydroxypropyl Methylcellulose MethocelE5 Dow Chemical 8.5 27 Company, Midland, MI Magnesium StearateMallinckrodt Inc., 1.0 3 St. Louis, MO D&C Yellow #10 Trace AmountEthanol Anhydrous (dried as solvent)

[0254] Dextromethorphan HBr, hydroxypropyl methylcellulose, PEO(MW=300,000), and D&C yellow #10 were mixed in a plastic bag for 1-2minutes. This powder mixture was added into the (5 qt) bowl of aplanetary mixer (Hobart Corp., Dayton, Ohio). The alcohol was added tothe powder mixture while mixing at low speed. The ingredients were mixedfor 10 minutes. The resulting granulation was removed from the bowl anddried at room temperature for 12 to 16 hours to remove all residualsolvent. The granulation was screened through a #20 mesh screen and wereput into a plastic bag. Magnesium stearate was added to the drygranules, followed by mixing for 3 minutes to form the second coreportion.

[0255] Cores were made from equal portions (by weight) of the first andsecond core portions as follows. A model M hydraulic Carver LaboratoryPress (Fred S. Carver, Inc., Hydraulic Equipment, Summit, N.J.) wasemployed. A round, concave punch and die unit having 0.4455″ diameterwas used for compression. The pseudoephedrine granulation for the firstcore portion was fed into the cavity mold of the press and was gentlytapped. Then the dextromethorphan granulation for the second coreportion was fed into the cavity overlying the pseudoephedrinegranulation. The granulations were pressed into a solid two-portion coreusing 1500 lb/sq. in. of compression force.

[0256] The first shell portion was made using the following ingredients:Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form CelluloseAcetate 398-10 Eastman Chemical 60.0 12.9 Company, Kingsport, TNPolyethylene Oxide Polyox ® WSR N-80 Union Carbide 20.0 4.3 (MW 200,000)Corporation, Danbury, CT Hydroxypropyl Methocel E5 Dow Chemical Company,20.0 4.3 Methylcellulose Midland, MI Acetone (dried as solvent)

[0257] The cellulose acetate was added to a beaker containing acetoneand mixed using a mixer until all powder was dissolved. An agitatingspeed of 500 rpm was used. Hydroxypropyl methylcellulose and PEO, whichwere screened through a #40 mesh screen, were added to the celluloseacetate solution, which was again mixed until all powder was dispersed.The first shell portion material was provided in flowable form.

[0258] The second shell portion was made using the followingingredients: Mg/Dosaage Ingredient Trade Name Manufacturer Weight % FormCellulose Acetate 398-10 Eastman Chemical 56.0 12.0 Company, Kingsport,TN Ammonio Methacrylate Eudragit ® RS 100 Roehm America 24.0 5.2Copolymer Type B Inc., Somerset, NJ Polyethylene Oxide Polyox ® WSR N-80Union Carbide 20.0 4.3 (MW 200,000) Corporation, Danbury, CT Acetone(dried as solvent)

[0259] The cellulose acetate was added into a beaker containing acetoneand was mixed using a mixer until all powder was dissolved. An agitatingspeed of 500 rpm was used. Ammonio methacrylate copolymer and PEO, whichwere screened through a #40 mesh screen, were added to the celluloseacetate solution, which was then mixed until all powder was dispersed.The second shell portion was provided in flowable form.

[0260] A thermal cycle molding module as described in Example 1 was usedto apply the first and second shell portions onto the core. The lowermold assembly portion was first cycled to a cold stage at 25° C. for 30seconds. The first shell portion material was added to the lower moldcavity. A two-portion core as described above was inserted into thelower mold cavity such that the first core portion, containingpseudoephedrine HCl sustained release granules, was inserted into thelower mold cavity. A blank upper mold assembly portion was mated thelower mold assembly portion. The mold assembly was then cycled to a hotstage at 85° C. for 2 minutes. Next, the assembly was cycled to a coldstage at 5° C. for 1 minute to harden the first shell portion. The blankupper mold assembly portion was then removed from the lower moldassembly portion.

[0261] The upper mold assembly portion was next cycled to a cold stageat 25° C. for 30 seconds. The second shell portion material was added tothe upper mold cavity. The half-coated core, with the first shellportion, was inserted into the upper mold cavity such that the uncoatedcore portion containing dextromethorphan HBr sustained release granulesrested within the upper mold cavity. The lower mold assembly portion,which had been maintained at 5° C., was then mated with the upper moldassembly portion. The upper mold assembly portion was then cycled to ahot stage at 85° C. for 2 minutes, followed by a cold stage at 5° C. for1 minute to harden the second shell portion. The lower mold assemblyportion was removed and the finished dosage form, a two-portion corecoated with two different shell portions, was ejected form the uppermold cavity. The weight gain due to the first and second shell portions,i.e. the difference in weights of the finished dosage form and theuncoated core, was recorded. The finished dosage form was dried at roomtemperature for 24 hours to remove all residual solvent.

[0262] The release profiles for the two active ingredients contained inthe dosage form of this example were compared with those of other dosageforms containing the same active ingredients. The results are shown inFIG. 4, which depicts the percent release of active ingredient versushours for the dosage form of Example 2 and other dosage forms. Curve (a)depicts the dissolution profile of the dextromethorphan HBr contained inthe second core portion of the finished dosage form of this example.Curve (b) depicts the dissolution profile of the dextromethorphan HBrfrom the uncoated core prepared according to this example, but withoutthe second shell portion. Curve (c) shows the dissolution profile ofpseudoephedrine HCl contained in the first core portion of the finisheddosage form of this Example. Curve (d) shows the dissolution profile ofpseudoephedrine HCl from the uncoated core prepared according to thisexample, but without the first shell portion.

[0263] All curves were derived using the following dissolutionapparatus: USP Type II apparatus (paddles, 50 RPM). Media: pH 7.2phosphate buffer at 37° C. Time points: Samples were removed at 0.5, 1,2, 4, 8, 12, 16, 20, and 24 hours to be analyzed for pseudoephedrineHCl, and dextromethorphan HBr. Dissolution samples were analyzed forthese two active ingredients versus a standard prepared at thetheoretical concentration for 100% released of each compound. Sampleswere analyzed using an HPLC equipped with a Waters® 717 Autoinjector anda Waters® 486 UV detector set at a wavelength of 214 nm. The mobilephase was prepared using 55% acetonitrile and 45% 18 mM Potassiumphosphate buffer. The injection volume was 50 μL with a run time ofapproximately 8 minutes an a pump flow of 2.0 mL/min. A Zorbax® 300-SCX(4.6 m×25 cm) column was used.

EXAMPLE 3

[0264] Dosage forms of the invention are made in a continuous processusing an apparatus comprising two thermal cycle molding modules linkedin series via a transfer device as described at pages 14-16 of copendingU.S. application Ser. No. 09/966,939, the disclosure of which isincorporated herein by reference. The dosage forms comprise a corecoated with a shell comprising a first portion and a second portion.

[0265] The core is made of a core flowable material comprising thefollowing ingredients: Mg/dosage Ingredient Trade Name ManufacturerWeight % Form Verapamil HCL Extended Verelan PM 300 mg Schwarz Pharma,Inc., 22.0 131 Release Pellets capsules Gainesville, GA PolyethyleneGlycol 3350 Carbowax ® Union Carbide 47.0 279 Corporation, Danbury, CTShellac Powder Mantrose-Haeuser 10.0 59 Company, Atteboro, MACroscarmellose Sodium Ac-Di-Sol ® FMC Corporation, 21.0 125 Newark, DE

[0266] PEG is heated to 70° C. and mixed until melted. The shellacpowder is screened through a #40 mesh screen, and then added to themolten PEG. The combined ingredients are mixed until all the powder isdispersed. Croscarmellose sodium is added next and the ingredients aremixed for an additional two minutes. The verapamil HCL pellets are thenadded, and the ingredients are mixed for five more minutes.

[0267] The first shell portion is made of a first shell portion flowablematerial comprising the following ingredients: Mg/Dosage IngredientTrade Name Manufacturer Weight % Form Pseudoephedrine HCl Crystal BASF30.0 53 PharmaChemikalien GmbH & Co. Ludwigshafen/Rhein. PolyethyleneGlycol 3350 Carbowax ® Union Carbide 50.0 89 Corporation, Danbury, CTPolyethylene Oxide Polyox ® WSR N-80 Union Carbide 15.0 27 (MW 200,000)Corporation, Danbury, CT Triethyl Citrate Morflex, Inc., 5.0 9Greensboro, NC

[0268] The PEG is heated to 70° C. and mixed until melted. The triethylcitrate is then added to the molten PEG and the mixture is mixed for oneminute. The PEO is added thereto, and the ingredients are mixed for 10additional minutes. The pseudoephedrine hydrochloride is added, and theingredients are mixed for two more minutes.

[0269] The second shell portion is made of a second shell portionflowable material comprising the following ingredients: Mg/DosageIngredient Trade Name Manufacturer Weight % Form Dextromethorphan HBrRoche Chemical 10.0 16 Co., Belvidere, NJ Polyethylene Glycol 3350Carbowax ® Union Carbide 50.0 77 Corporation, Danbury, CT PolyethyleneOxide Polyox ® WSR N-80 Union Carbide 15.0 23 (MW 200,000) Corporation,Danbury, CT Shellac Powder Mantrose-Haeuser 10.0 16 Company, Atteboro,MA Croscarmellose Sodium Ac-Di-Sol ® FMC Corporation, 5.0 8 Newark, DETriethyl Citrate Morflex, Inc., 10.0 16 Greensboro, NC

[0270] The PEG is heated to 70° C. and mixed until melted. The shellacpowder is screened through a #40 mesh screen, and then added to themolten PEG. The combined ingredients are mixed until all powder isdispersed. The triethyl citrate is added next and the ingredients aremixed for one minute. PEO is added to the mixture and the ingredientsare again mixed for 10 minutes. Croscarmellose sodium is then addedfollowed by mixing for two additional minutes. Finally, dextromethorphanHBr is added and the ingredients are mixed for two more minutes.

[0271] The thermal cycle molding modules have the general configurationshown in FIG. 3 and pages 27-51 of copending U.S. application Ser. No.09/966,497, which depicts a thermal cycle molding module 200 comprisinga rotor 202 around which a plurality of mold units 204 are disposed. Thethermal cycle molding modules include reservoirs 206 (see FIG. 4) forholding the core flowable material, the first shell portion flowablematerial, and the second shell portion flowable material. In addition,each thermal cycle molding module is provided with a temperature controlsystem for rapidly heating and cooling the mold units. FIGS. 55 and 56of pending U.S. application Ser. No. 09/966,497 depict the temperaturecontrol system 600.

[0272] The cores are made in a first thermal cycle molding module, whichis linked via a transfer device to a second thermal cycle moldingmodule. The first thermal cycle molding module has the specificconfiguration shown in FIG. 26A of copending U.S. application Ser. No.09/966,497. The first thermal cycle molding module comprises center moldassemblies 212 and upper mold assemblies 214 as shown in FIG. 26C ofcopending U.S. application Ser. No. 09/966,497, which mate to form moldcavities having a tablet shape. As rotor 202 rotates, the opposingcenter and upper mold assemblies close. Core flowable material, which isheated to a flowable state in reservoir 206, is injected into theresulting mold cavities. The temperature of the core flowable materialis then decreased, hardening the core flowable material intotablet-shaped cores. The mold assemblies open and eject the cores, whichare received by the first transfer device.

[0273] The transfer device has the structure shown as 300 in FIG. 3 anddescribed on pages 51-57 of copending U.S. application Ser. No.09/966,414, the disclosure of which is incorporated by reference. Itcomprises a plurality of transfer units 304 attached in cantileverfashion to a belt 312 as shown in FIGS. 68 and 69. The transfer devicerotates and operates in sync with the thermal cycle molding modules towhich it is coupled. Transfer units 304 comprise retainers 330 forholding the cores as they travel around the transfer device.

[0274] The transfer device transfers the cores to the second thermalcycle molding module, which applies the shell to the cores. The secondthermal cycle molding module is of the type shown in FIG. 28A ofcopending U.S. application Ser. No. 09/966,497. The mold units 204 ofthe second thermal cycle molding module comprise upper mold assemblies214, rotatable center mold assemblies 212 and lower mold assemblies 210as shown in FIG. 28C. Cores are continuously transferred to the moldassemblies, which then close over the cores.

[0275] Coating is performed in two steps, the first and second shellportions being applied separately as shown in the flow diagram of FIG.28B of copending U.S. application Ser. No. 09/966,497. In a first step,first shell portion flowable material, heated to a flowable state inreservoir 206, is injected into the mold cavities created by the closedmold assemblies. The temperature of the first shell portion flowablematerial is then decreased, hardening it over half the core. The moldassemblies separate, the center mold assembly rotates, and then the moldassemblies again close. In a second step, second shell portion flowablematerial, heated to a flowable state in reservoir 206, is injected intothe mold cavities. The temperature of the second shell portion flowablematerial is then decreased, hardening it over the other half of thecore. The mold assemblies separate, and the finished dosage forms areejected from the apparatus.

[0276] Although this invention has been illustrated by reference tospecific embodiments, it will be apparent to those skilled in the artthat various changes and modifications may be made which clearly fallwithin the scope of this invention.

The invention claimed is:
 1. A dosage form comprising: (a) at least oneactive ingredient; (a) a core; and (b) a shell which resides upon atleast a portion of the core, wherein the shell is substantially free ofpores having a diameter of 0.5 to 5.0 microns; the shell comprises afirst shell portion and a second shell portion which are compositionallydifferent; and the dosage form provides a modified release profile ofthe active ingredient upon contacting of the dosage form with a liquidmedium.
 2. The dosage form of claim 1, in which at least one of thefirst or second shell portions comprises means for modifying the releaseprofile of an active ingredient contained either in (i) the core or (ii)the shell portion comprising the means for modifying the release profileupon contacting of the dosage form with a liquid medium.
 3. The dosageform of claim 1 in which at least one of the first or second shellportions comprises an active ingredient.
 4. The dosage form of claim 1,in which the first and second shell portions each comprise an activeingredient.
 5. The dosage form of claim 1, in which at least one of thefirst or second shell portions comprises an active ingredient which isimmediately released therefrom upon contacting of the dosage form with aliquid medium.
 6. The dosage form of claim 1, in which at least one ofthe first or second shell portions provides modified release of at leastone active ingredient contained therein.
 7. The dosage form of claim 1,in which at least one of the first or second shell portions comprises atleast one active ingredient, and the release of the active ingredientcontained in the shell portion is sustained, prolonged, extended, orretarded upon contacting of the dosage form with a liquid medium.
 8. Thedosage form of claim 4, in which the first and second shell portionseach provide different release profiles for the active ingredientscontained therein upon contacting of the dosage form with a liquidmedium.
 9. The dosage form of claim 1, in which at least one of thefirst or second shell portions provides modified release of at least oneactive ingredient contained in the underlying core or portion thereof.10. The dosage form of claim 1, in which the core comprises particlescomprising the active material.
 11. The dosage form of claim 6, in whichthe particles comprise a coating capable of providing a modified releaseprofile of the active ingredient in the particles upon contacting of thecore with a liquid medium.
 12. The dosage form of claim 1, in which thecore comprises a first core portion and a second core portion, at leastone core portion comprises at least one active ingredient, and at leastone active ingredient contained in the first or second core portionexhibits a modified release profile upon contacting of the dosage formwith a liquid medium.
 13. The dosage form of claim 1, in which the corecomprises a first core portion and a second core portion, at least onecore portion comprises at least one active ingredient, and the first orsecond core portion comprises a material which provides a modificationto the release of an active ingredient contained therein upon contactingof the dosage form with a liquid medium.
 14. The dosage form of claim 1,in which the core comprises a first core portion and a second coreportion, at least one core portion comprises at least one activeingredient, and the first or second shell portion comprises a materialwhich provides a modification to the release of an active ingredientcontained in the underlying core portion upon contacting of the dosageform with a liquid medium.
 15. The dosage form of claim 1, in which thecore comprises a first core portion and a second core portion, at leastone core portion comprises at least one active ingredient, and therelease of the active ingredient contained in the core portion isdelayed upon contacting of the dosage form with a liquid medium.
 16. Thedosage form of claim 1, in which the core comprises a first core portionand a second core portion, and at least one core portion comprises atleast one active ingredient, and the release of the active ingredientcontained in the core portion is sustained, prolonged, extended, orretarded upon contacting of the dosage form with a liquid medium. 17.The dosage form of claim 1, in which at least one of the first or secondcore portions comprises an active ingredient which is immediatelyreleased therefrom upon breach of the surrounding shell portion andcontacting of the core portion with a liquid medium.
 18. The dosage formof claim 1, in which the core comprises a first core portion and asecond core portion, each core portion comprises an active ingredient,and each of the active ingredients exhibits a modifed release profileupon contacting of the dosage form with a liquid medium.
 19. The dosageform of claim 18, in which the release profiles of the activeingredients in the first and second core portions are substantiallysimilar.
 20. The dosage form of claim 18, in which the release profilesof the first and second core portions are substantially different. 21.The dosage form of claim 1, in which the core comprises a first coreportion and a second core portion, only one of the first or second coreportions comprises an active ingredient, and the active ingredientexhibits a modifed release profile upon contacting of the dosage formwith a liquid medium.
 22. The dosage form of claim 1, in which the coreis a bi-layer tablet.
 23. The dosage form of claim 1, in which at leastone of the first or second core portions comprises particles comprisingat least one active ingredient.
 24. The dosage form of claim 23, inwhich the particles comprise a coating capable of providing a modifedrelease profile of the active ingredient in the particles uponcontacting of the core with a liquid medium.
 25. The dosage form ofclaim 1, in which the core is substantially free of pores having adiameter of 0.5-5.0 microns.
 26. A dosage form comprising: (a) at leastone active ingredient; (b) a core comprising first and second coreportions; and (c) a shell portion which surrounds at least one of thefirst or second core portions.
 27. A dosage form comprising: (a) atleast one active ingredient; (b) a core comprising first and second coreportions; and (c) a shell portion which surrounds only the first coreportion, wherein the second core portion is not enclosed by a shellportion, and the second core portion is exposed immediately to theliquid medium upon contact of the dosage form with a liquid medium. 28.A dosage form comprising: (a) at least one active ingredient; (b) a corecomprising first and second core portions; and (c) a shell which residesupon at least a portion of the core, wherein the shell comprises firstand second shell portions such that the first shell portion resides uponat least a portion of the first core portion and the second shellportion resides upon at least a portion of the second core portion, andat least one of the first or second core portions or first or secondshell portions provides a modified release profile of an activeingredient upon contacting of the dosage form with a liquid medium. 29.The dosage form of claim 28, in which the first core portion comprises afirst active ingredient, and the second core portion does not comprisean active ingredient.
 30. The dosage form of claim 28, in which thefirst core portion comprises a first active ingredient, and the secondcore portion comprises a second active ingredient.
 31. The dosage formof claim 30, in which the first shell portion provides for modifiedrelease of the first active ingredient, and the second shell portionprovides for modified release of the second active ingredient.
 32. Thedosage form of claim 30, in which the first shell portion provides forimmediate release of the first active ingredient, and the second shellportion provides for modified release of the second active ingredient.33. The dosage form of claim 28, in which the first core portioncomprises a first active ingredient, the second core portion comprises asecond active ingredient, the first shell portion comprises a thirdactive ingredient, and the second shell portion comprises a fourthactive ingredient.
 34. The dosage form of claim 1 or claim 28, whereinthe dosage form comprises means for providing an erosion controlledrelease profile of at least one active ingredient.
 35. The dosage formof claim 34, wherein the dosage form comprises means for providing anerosion controlled release profile of an active ingredient contained inthe core.
 36. The dosage form of claim 1 or claim 28, wherein the dosageform comprises means for providing a diffusion controlled releaseprofile of at least one active ingredient.
 37. The dosage form of claim36, wherein the dosage form comprises means for providing a diffusioncontrolled release profile of an active ingredient contained in thecore.
 38. The dosage form of claim 1 or claim 28, wherein the dosageform comprises means for providing an immediate release profile for anactive ingredient contained in the shell.
 39. The dosage form of claim 1or claim 28, wherein the dosage form comprises means for providing adelayed release profile for an active ingredient contained in the core.40. The dosage form of claim 1 or claim 28, wherein the dosage formcomprises means for providing an immediate release profile of an activeingredient contained in the core upon a breach of the shell by theliquid medium.
 41. The dosage form of claim 28, in which at least one ofthe first or second core portions is substantially free of pores havinga diameter of 0.5-5.0 microns.
 42. The dosage form of claim 28, in whichat least one of the first or second shell portions is substantially freeof pores having a diameter of 0.5-5.0 microns.
 43. The dosage form ofclaim 1 or claim 28, wherein the dosage form comprises means forproviding a pulsatile release profile of at least one active ingredient.44. The dosage form of claim 1 or claim 28, wherein one or more shellportions prevent release therethrough of an active ingredient containedin the underlying core or core portion.
 45. The dosage form of claim 1or claim 28, wherein at least one of the first or second shell portionscomprises a thermal-reversible carrier selected from the groupconsisting of polyethylene glycol, polyethylene oxide and combinationsthereof.
 46. The dosage form of claim 1 or claim 28, wherein at leastone of the first or second shell portions comprises a release modifyingexcipent selected from the group consisting of shellac,hydroxypropylmethylcellulose, polyethylene oxide, ammonio methacrylatecopolymer type B, and combinations thereof.
 47. The dosage form of claim1 or claim 28, wherein at least one of the first or second shellportions comprises a film-former selected from the group consisting ofcellulose acetate, ammonio methacrylate copolymer type B, shellac,hydroxypropylmethylcellulose, and combinations thereof.
 48. The dosageform of claim 1 or claim 28, wherein at least one of the first or secondshell portions comprises a swellable erodible hydrophilic materialselected from the group consisting of selected from cross-linkedpolyvinyl pyrrolidone, cross-linked agar, cross-linkedcarboxymethylcellose sodium, and combinations thereof.
 49. The dosageform of claim 1 or claim 28, wherein at least one of the first or secondshell portions further comprises a plasticizer.
 50. The dosage form ofclaim 1 or claim 28, wherein at least one of the first or second shellportions comprises a pore former.
 51. The dosage form of claim 1 orclaim 28, further comprising an outer coating which covers at least aportion of the shell.